Analytical basis for the determination of the lacunar–canalicular permeability of bone using cyclic loading

An analytical model for the determination of the permeability in the lacunar-canalicular porosity of bone using cyclic loading is described in this contribution. The objective of the analysis presented is to relate the lacunar-canalicular permeability to a particular phase angle that is measurable when the bone is subjected to infinitesimal cyclic strain. The phase angle of interest is the lag angle between the applied strain and the resultant stress. Cyclic strain causes the interstitial fluid to move. This movement is essential for the viability of osteocytes and is believed to play a major role in the bone mechanotransduction mechanism. However, certain bone fluid flow properties, notably the permeability of the lacunar-canalicular porosity, are still not accurately determined. In this paper, formulas for the phase angle as a function of permeability for infinitesimal cyclic strain are presented and mathematical expressions for the storage modulus, loss modulus, and loss tangent are obtained. An accurate determination of the PLC permeability will improve our ability to understand mechanotransduction and mechanosensory mechanisms, which are fundamental to the understanding of how to treat osteoporosis, how to cope with microgravity in long-term manned space flights, and how to increase the longevity of prostheses that are implanted in bone tissue.     

Analysis of bone–prosthesis interface micromotion for cementless tibial prosthesis fixation and the influence of loading conditions

A lack of initial stability of the fixation is associated with aseptic loosening of the tibial components of cementless knee prostheses. With sufficient stability after surgery, minimal relative motion between the prosthesis and bone interfaces allows osseointegation to occur thereby providing a strong prosthesis-to-bone biological attachment. Finite element modelling was used to investigate the bone–prosthesis interface micromotion and the relative risk of aseptic loosening. It was anticipated that by prescribing different joint loads representing gait and other activities, and the consideration of varying tibial–femoral contact points during knee flexion, it would influence the computational prediction of the interface micromotion. In this study, three-dimensional finite element models were set up with applied loads representing walking and stair climbing, and the relative micromotions were predicted. These results were correlated to in-vitro measurements and to the results of prior retrieval studies. Two load conditions, (i) a generic vertical joint load of 3×body weight with 70%/30% M/L load share and antero-posterior/medial-lateral shear forces, acted at the centres of the medial and lateral compartments of the tibial tray, and (ii) a peak vertical joint load at 25% of the stair climbing cycle with corresponding antero-posterior shear force applied at the tibial–femoral contact points of the specific knee flexion angle, were found to generate interface micromotion responses which corresponded to in-vivo observations. The study also found that different loads altered the interface micromotion predicted, so caution is needed when comparing the fixation performance of various reported cementless tibial prosthetic designs if each design was evaluated with a different loading condition.     

One mechanostat or many? Modifications of the site-specific response of bone to mechanical loading by nature and nurture

The concept of the mechanostat was not new in 1983, when Harold Frost coined the term to describe a mechanism by which bone responded to habitual exercise and changes in loading with structurally appropriate alterations in bone architecture. However, the word "mechanostat" has a meaning that is immediately apparent, and its adoption has led to a much wider appreciation of the process of functional adaptation by other scientists than those whose primary research focus is in the biology of adaptation. One problem exists though: it is widely thought that in a single individual, there is a setting for the mechanostat, just as a single thermostat might set the temperature for a whole house, and this is reflected in the idea that bones throughout the skeleton require a specific strain magnitude for maintenance. Increases in loading above that threshold are expected to induce bone formation and a stiffer structure that then experiences again the habitual strain magnitude. Reductions in strain magnitude supposedly induce resorption to reduce tissue mass and architectural properties so that the lower loading restores habitual strain magnitude. That widely held belief of a single unifying number of strain is fundamentally flawed. The purpose of this article is to explain the real basis of the mechanostat; that the skeleton responds to a complex strain stimulus, made up of numerous different parameters, of which peak magnitude is only one, and that the strain stimulus is different in different parts of the skeleton, so there is no universal number to describe a tissue strain magnitude that underlies the mechanostat's setting. Furthermore, males and females have different responses to loading, and those responses change in response to many factors including genetic constitution, age, concomitant disease, nutrient availability, and exposure to drugs or biochemicals. In summary then, there is not a single mechanostat controlling the skeleton of each of us. At a fundamental tissue level, small functional units of bone each have their own multifactorial threshold target strain stimuli for a given set of dynamic modifying influences. Understanding the biology behind the way that each of these mechanostats functions independently is likely to have pervasive consequences on our ability to control bone mass by manipulation of loading, either directly through different exercise regimens, or in a targeted manner using tailored site and individual specific pharmaceuticals.     

Finite element analysis of dental implant loading on atrophic and non-atrophic cancellous and cortical mandibular bone – a feasibility study

The first aim of this study was to assess displacements and micro-strain induced on different grades of atrophic cortical and trabecular mandibular bone by axially loaded dental implants using finite element analysis (FEA). The second aim was to assess the micro-strain induced by different implant geometries and the levels of bone-to-implant contact (BIC) on the surrounding bone. Six mandibular bone segments demonstrating different grades of mandibular bone atrophy and various bone volume fractions (from 0.149 to 0.471) were imaged using a micro-CT device. The acquired bone STL models and implant (Brånemark, Straumann, Ankylos) were merged into a three-dimensional finite elements structure. The mean displacement value for all implants was 3.1±1.2 µm. Displacements were lower in the group with a strong BIC. The results indicated that the maximum strain values of cortical and cancellous bone increased with lower bone density. Strain distribution is the first and foremost dependent on the shape of bone and architecture of cancellous bone. The geometry of the implant, thread patterns, grade of bone atrophy and BIC all affect the displacement and micro-strain on the mandible bone. Preoperative finite element analysis could offer improved predictability in the long-term outlook of dental implant restorations.     

Are campylobacters now capable of carbo‐loading?

Campylobacters are a leading cause of gastrointestinal morbidity worldwide and the majority of human infections are triggered by eating foods contaminated with Campylobacter jejuni or Campylobacter coli. Campylobacters are equally notorious for their ability to mimic human glycoconjugate structures and for their capacity to synthesize both N‐ and O‐linked glycoproteins. These species were once considered to be asaccharolytic, but it was recently shown that several strains possess a pathway for fucose uptake and metabolism, providing those isolates with a competitive advantage in vivo. Vorwerk et al. have now demonstrated through isotopologue profiling that certain strains of C. coli and C. jejuni are capable of glucose catabolism through the Entner‐Doudoroff and pentose phosphate pathways. However, unlike the fate of fucose that has only been shown to be used for nutrition, glucose can be metabolized or incorporated into select amino acids and glycoconjugates. This discovery now provides researchers with the opportunity to introduce metabolically labeled sugars into campylobacters to study glycoconjugate biosynthesis within the cell. In addition, Vorwerk et al. add to the metabolic arsenal of campylobacters further highlighting the nutritional diversity among strains, even within the same species.     

Role of carotenoid β-cryptoxanthin in bone homeostasis

Bone homeostasis is maintained through a balance between osteoblastic bone formation and osteoclastic bone resorption. Aging induces bone loss due to decreased osteoblastic bone formation and increased osteoclastic bone resorption. Osteoporosis with its accompanying decrease in bone mass is widely recognized as a major public health problem. Nutritional factors may play a role in the prevention of bone loss with aging. Among various carotenoids (carotene and xanthophylls including beta (β)-cryptoxanthin, lutein, lycopene, β-carotene, astaxanthin, and rutin), β-cryptoxanthin, which is abundant in Satsuma mandarin orange (Citrus unshiu MARC.), has been found to have a stimulatory effect on bone calcification in vitro. β-cryptoxanthin has stimulatory effects on osteoblastic bone formation and inhibitory effects on osteoclastic bone resorption in vitro, thereby increasing bone mass. β-cryptoxanthin has an effect on the gene expression of various proteins that are related osteoblastic bone formation and osteoclastic bone resororption in vitro. The intake of β-cryptoxanthin may have a preventive effect on bone loss in animal models for osteoporosis and in healthy human or postmenopausal women. Epidemiological studies suggest a potential role of β-cryptoxanthin as a sustainable nutritional approach to improving bone health of human subjects. β-Cryptoxanthin may be an osteogenic factor in preventing osteoporosis in human subjects.     

Analysis of the musculoskeletal loading of the thumb during pipetting – A pilot study

Previous epidemiological studies indicate that the use of thumb-push mechanical pipettes is associated with musculoskeletal disorders (MSDs) in the hand. The goal of the current study was to analyze the loading in the muscle–tendon units in the thumb during pipetting. The hand is modeled as a multi-body linkage system and includes four fingers (index, long, ring, and little finger), a thumb, and a palm segment. Since the current study is focused on the thumb, the model includes only nine muscles attached to the thumb via tendons. The time-histories of joint angles and push force at the pipette plunger during pipetting were determined experimentally and used as model input; whereas forces in the muscle–tendon units in the thumb were calculated via an inverse dynamic approach combined with an optimization procedure. Results indicate that all nine muscles have force outputs during pipetting, and the maximal force was in the abductor pollicis brevis (APB). The ratio of the mean peak muscle force to the mean peak push force during the dispensing cycle was approximately 2.3, which is comparable to values observed in grasping tasks in the literature. The analysis method and results in the current study provide a mechanistic understanding of MSD risk factors associated with pipetting, and may be useful in guiding ergonomic designs for manual pipettes.     

How do trabeculae affect the calculation of structural properties of bone?

One difficulty that arises in an analysis of the cross-sectional properties of bone is whether to include cancellous bone in the analysis. The purpose of this paper is to determine how different amounts of cancellous bone affect the measurement of structural properties of bone cross-sections. Thirty-two tibial and femoral cross-sections were chosen at random from a series of cross-sectioned nonhuman primate bones. Geometrical properties were calculated for the cross-sections, and torsional and bending stress analyses were performed. The results suggest that the effect of including cancellous bone in the analysis is closely related to the amount of bone, where it lies within the cross-section, and the type of analysis performed. Including cancellous bone in calculations of structural properties of bone cross-sections may cause the strength and stiffness of the bone to be exaggerated.     

Organ printing: the future of bone regeneration?

In engineered bone grafts, the combined actions of bone-forming cells, matrix and bioactive stimuli determine the eventual performance of the implant. The current notion is that well-built 3D constructs include the biological elements that recapitulate native bone tissue structure to achieve bone formation once implanted. The relatively new technology of organ/tissue printing now enables the accurate 3D organization of the components that are important for bone formation and also addresses issues, such as graft porosity and vascularization. Bone printing is seen as a great promise, because it combines rapid prototyping technology to produce a scaffold of the desired shape and internal structure with incorporation of multiple living cell types that can form the bone tissue once implanted.     

Numerical modeling of bone tissue adaptation—A hierarchical approach for bone apparent density and trabecular structure

In this work, a three-dimensional model for bone remodeling is presented, taking into account the hierarchical structure of bone. The process of bone tissue adaptation is mathematically described with respect to functional demands, both mechanical and biological, to obtain the bone apparent density distribution (at the macroscale) and the trabecular structure (at the microscale). At global scale bone is assumed as a continuum material characterized by equivalent (homogenized) mechanical properties. At local scale a periodic cellular material model approaches bone trabecular anisotropy as well as bone surface area density. For each scale there is a material distribution problem governed by density-based design variables which at the global level can be identified with bone relative density. In order to show the potential of the model, a three-dimensional example of the proximal femur illustrates the distribution of bone apparent density as well as microstructural designs characterizing both anisotropy and bone surface area density. The bone apparent density numerical results show a good agreement with Dual-energy X-ray Absorptiometry (DXA) exams. The material symmetry distributions obtained are comparable to real bone microstructures depending on the local stress field. Furthermore, the compact bone porosity is modeled giving a transversal isotropic behavior close to the experimental data. Since, some computed microstructures have no permeability one concludes that bone tissue arrangement is not a simple stiffness maximization issue but biological factors also play an important role.     

Fluid–structure interaction (FSI) modeling of bone marrow through trabecular bone structure under compression

Biomechanics and Modeling in Mechanobiology - The present study has sought to investigate the fluid characteristic and mechanical properties of trabecular bone using fluid–structure...     

The effect of ribose pre-treatment of cortical bone on γ-irradiation sterilization effectiveness

Reconstruction of large skeletal defects is a significant and challenging issue. Tissue banks often use γ-irradiation (15–35 kGy) to sterilize bone allografts, which, however, drastically impairs the post-yield mechanical properties. In previous studies, we reported the development of a method that protects human bone collagen connectivity through ribose crosslinking while still undergoing γ-irradiation. Given these promising results, the next step was to determine if the presence of ribose within the bone tissue would interfere with the effectiveness of the γ-irradiation sterilization against bacteria. This study had two stages. The aim of the first stage was to assess the protective effect of ribose in solution using a Bacillus pumilus spore strip model. The aim of the second stage was to assess the protective effect of ribose (R) on spores within a human cortical bone model in comparison to conventionally irradiated bone (I). Treatment of B. pumilus spore strips with ribose in solution led to temperature-dependent effects on spore viability versus spore strips treated with PBS alone. Ribose solution at 60 °C led to a notable two logs decrease in spore count relative to PBS at 60 °C. In the human bone model, the number of spores in the I and R groups were greatly decreased in comparison to the non-irradiated N group. No spore colonies were detected in the R group (n = 4) whereas two of the four plates of group I formed colonies. This study provides evidence that the method of pre-treating bone with ribose crosslinking prior to irradiation sterilization, while improving irradiation sterilized bone allograft quality, also may improve the effectiveness of the sterilization process.     

Down-regulation of β3-integrin inhibits bone metastasis of small cell lung cancer

Bone is one of the most frequent targets of small cell lung cancer (SCLC) metastasis, but the molecular mechanism remains unclear. β3-integrin plays an important role in invasion of various kinds of tumors. Yet, its role in bone-metastasis of SCLC is still unknown. In this study, we first examined the expression of β3-integrin in SBC-5 and SBC-3 cells by real-time PCR, western blot and immunofluorescence. We found that, compared to none bone-metastatic SBC-3 cells, β3-integrin was highly expressed in SBC-5 cells, a specific bone-metastatic SCLC cells line characterized in our previous study. We next constructed β3-integrin siRNA and transfected SBC-5 cell line, and found that β3-integrin siRNA significantly down-regulated the β3-integrin mRNA level and protein expression in SBC-5 cell line. We further found that inhibition of β3-integrin significantly reduced tumor cell proliferation and induced apoptosis. In addition, the β3-integrin down-regulated cells presented significant decrease in cell adhesion, migration and invasion activity. Our results suggest the β3-integrin has an essential effect on tumor cell proliferation and progression, and may be a potential therapeutic target for the prevention of skeletal metastases of lung cancer.     

Sex difference in the accumulation of d-β-aminoisobutyrate in organs of mouse after thymine loading

The concentration of d--aminoisobutyric acid (d-BAIB) in the liver and kidney was twice as high and dropped more slowly in the female mouse than in the male after an intraperitoneal injection of thymine. The concentration of -alanine, formed from uracil by the same enzyme system catalyzing formation of d-BAIB from thymine, was not different in the liver and kidney of both sexes after an intraperitoneal injection of uracil. After the intraperitoneal injection of d-BAIB, the concentration of BAIB in male liver decreased faster than that in female liver. Inhibition of d-BAIB: pyruvate aminotransferase caused by injection of d-cycloserine resulted in a significant increase in the concentration of BAIB in liver of both sexes after injection of thymine, but the concentration dropped more rapidly in the male. The activity of d-BAIB: pyruvate aminotransferase was not different in the livers of male and femalemice. Under the action of probenecid, an inhibitor of active transport systems, the sex difference in accumulation and disappearance of the amino acid in the liver was not observed. This suggested that the excretion of BAIB is more active in the renal tubules of the male mouse than in those of the female. However, the amount of BAIB excreted in the urine after injection of thymine was larger in the female mice than in the male mice. There may be another probenecid-sensitive enzyme for the disposal of BAIB in male mice.     

Identification of the disease-causing gene in sclerosteosis--discovery of a novel bone anabolic target?

Genetic studies recently unraveled the genetic cause of sclerosteosis, a rare skeletal dysplasia characterized by a generalized increase in bone mass. Different loss-of-function mutations were identified in SOST, a gene with no homology to any known gene. This SOST gene is also involved in the pathogenesis of van Buchem disease, a disorder closely resembling sclerosteosis, since a 52-kb deletion located downstream of SOST is found in patients diagnosed with this condition. Molecular studies showed a very restricted expression pattern of SOST and its gene product, sclerostin, with areas in the bone tissue, more precisely in cells of the osteoblast lineage, being the major sites of expression. Sclerostin is a secreted protein with a cysteine knot motif. In vitro studies demonstrated that sclerostin acts as a modulator of BMP signaling by binding to different members of the BMP growth factor family and acting on downstream BMP signal transduction events. The important function of sclerostin in bone metabolism has also been proven in vivo by the osteopenic phenotype of transgenic mice overexpressing SOST in bone. The identification of sclerostin as an important protein in bone metabolism opens new perspectives for the development of anabolic therapeutics to prevent and treat osteoporosis.     

Deformation of articular cartilage during static loading of a knee joint – Experimental and finite element analysis

Novel conical beam CT-scanners offer high resolution imaging of knee structures with i.a. contrast media, even under weight bearing. With this new technology, we aimed to determine cartilage strains and meniscal movement in a human knee at 0, 1, 5, and 30 min of standing and compare them to the subject-specific 3D finite element (FE) model. The FE model of the volunteer?s knee, based on the geometry obtained from magnetic resonance images, was created to simulate the creep. The effects of collagen fibril network stiffness, nonfibrillar matrix modulus, permeability and fluid flow boundary conditions on the creep response in cartilage were investigated. In the experiment, 80% of the maximum strain in cartilage developed immediately, after which the cartilage continued to deform slowly until the 30 min time point. Cartilage strains and meniscus movement obtained from the FE model matched adequately with the experimentally measured values. Reducing the fibril network stiffness increased the mean strains substantially, while the creep rate was primarily influenced by an increase in the nonfibrillar matrix modulus. Changing the initial permeability and preventing fluid flow through noncontacting surfaces had a negligible effect on cartilage strains. The present results improve understanding of the mechanisms controlling articular cartilage strains and meniscal movements in a knee joint under physiological static loading. Ultimately a validated model could be used as a noninvasive diagnostic tool to locate cartilage areas at risk for degeneration.     

Mechanical loading prevents the stimulating effect of IL-1β on osteocyte-modulated osteoclastogenesis

Ever since the technique of coaxing ordinary skin cells into becoming pluripotent stem cells (iPSCs) has been developed, which have the potential to become any cell or tissue in the body, efforts were made to improve the approach because some major challenges. Increasing evidence suggests that several microRNAs (miRNAs) are involved in early embryonic development and embryonic stem cell formation, known as embryonic stem cell (ESC)-specific miRNAs, particularly the miR-302 family. We summarized here a novel approach to generate iPSCs by using miR-302 and its related miRNAs such as miR-367. The development of this miR-302/367-mediated iPSC (termed mirPSC) may provide tools to deal with the obstacles facing some current iPSC reprogramming methods. The mechanism by which miR-302/367 induce iPSC reprogramming is proposed.