Treatment of osteoporosis with human parathyroid peptide and observations on effect of sodium fluoride.

OBJECTIVE--To evaluate the need for a randomised study of treatment of spinal osteoporosis with human parathyroid peptide in the secondary prevention of crush fractures; to study the effect of human parathyroid hormone peptide 1-34 plus sex hormones on vertebral body cancellous bone; and, separately, to determine the effect of relatively low doses of sodium fluoride plus calcium on spinal bone mineral density. DESIGN--Open study of patients with primary or postmenopausal osteoporosis. All patients had serial bone densitometry of the spine by quantitative computed tomography and dual photon absorptiometry as well as serial densitometry of the radial midshaft (cortical) and radial distal (trabecular) bone by quantitative computed tomography. Changes in the spinal bone not forming the spongiosa of the vertebral bodies ("cortical" bone) were determined from the difference between the two axial measurements, after correction to the same units of measurement. SETTING--Northwick Park Hospital and Medical Research Council Clinical Research Centre. PATIENTS--24 Patients who fulfilled the conventional criteria for type 1 (vertebral) osteoporosis not secondary to recognised causes other than sex hormone deficiency and with at least one crush or wedge vertebral fracture and a spinal bone density (quantitative computed tomography) less than 80 mg/cm3 or two or more fractures. Twelve patients received human parathyroid peptide and 12 sodium fluoride; they were not randomised. MAIN OUTCOME MEASURES--Trends in axial and peripheral bone mass values determined by linear, time dependent regression analyses. RESULTS--The patients receiving the peptide showed a substantial increase in vertebral spongiosa (mean 25.6 mg/cm2 two years after the start of treatment). No significant changes were seen in spinal cortical or radial bone density. The patients receiving sodium fluoride showed roughly equal increases in cancellous and cortical bone over the same period (mean increase in vertebral spongiosa 16.1 mg/cm3). No significant changes were seen in radial bone. CONCLUSIONS--Treatment of postmenopausal women with human parathyroid peptide selectively increases spinal cancellous bone density by amounts that may prove useful in secondary prevention. Peptide treatment should now be tested in a randomised study in which the important end point is prevention of fractures as the usefulness of sodium fluoride in this context is doubtful.     

Assessment of the Effect of Mesh Density on the Material Property Discretisation Within QCT Based FE Models: A Practical Example Using the Implanted Proximal Tibia

A three-dimensional, quantitative computed tomography based finite element model of a proximal implanted tibia was analysed in order to assess the effect of mesh density on material property discretisation and the resulting influence on the predicted stress distribution. The mesh was refined on the contact surfaces (matched meshes) with element sizes of 3, 2, 1.4, 1 and 0.8 mm. The same loading conditions were used in all models (bi-condylar load: 60% medial, 40% lateral). Significant variations were observed in the modulus distributions between the coarsest and finest mesh densities. Poor discretisation of the material properties also resulted in poor correlations of the stresses and risk ratios between the coarsest and finest meshes. Little difference in Young's modulus, von Mises stress and risk ratio distributions were observed between the three finest models; hence, it was concluded that for this particular case an element size of 1.4 mm on the contact surfaces was enough to properly describe the stiffness, stress and risk ratio distributions within the bone. Poor convergence of the material property distribution occurred when the element size was significantly larger than the pixel size of the source CT data. It was concluded that unless there is convergence in the Young's modulus distribution, convergence of the stress field or of other parameters of interest will not occur either.     

Assessment of vertebral wedge strength using cancellous textural properties derived from digital tomosynthesis and density properties from dual energy X-ray absorptiometry and high resolution computed tomography

The purpose of this study was to examine the potential of digital tomosynthesis (DTS) derived cancellous bone textural measures to predict vertebral strength under conditions simulating a wedge fracture. 40 vertebral bodies (T6, T8, T11, and L3 levels) from 5 male and 5 female cadaveric donors were utilized. The specimens were scanned using dual energy X-ray absorptiometry (DXA) and high resolution computed tomography (HRCT) to obtain measures of bone mineral density (BMD) and content (BMC), and DTS to obtain measures of bone texture. Using a custom loading apparatus designed to deliver a nonuniform displacement resulting in a wedge deformity similar to those observed clinically, the specimens were loaded to fracture and their fracture strength was recorded. Mixed model regressions were used to determine the associations between wedge strength and DTS derived textural variables, alone and in the presence of BMD or BMC information. DTS derived fractal, lacunarity and mean intercept length variables correlated with wedge strength, and individually explained up to 53% variability. DTS derived textural variables, notably fractal dimension and lacunarity, contributed to multiple regression models of wedge strength independently from BMC and BMD. The model from a scan orientation transverse to the spine axis and in the anterior-posterior view resulted in highest explanatory capability (R²_adj = 0.91), with a scan orientation parallel to the spine axis and in the lateral view offering an alternative (R²_adj = 0.88). In conclusion, DTS can be used to examine cancellous texture relevant to vertebral wedge strength, and potentially complement BMD in assessment of vertebral fracture risk.     

Apparent Young's modulus of human radius using inverse finite-element method

The ability to assess the elastic and failure properties of cortical bone at the radial diaphysis has a clinical importance. A new generation of quantitative ultrasound (QUS) devices and peripheral quantitative computed tomography (p-QCT) has been developed to assess non-invasively bone material and structural properties at the distal radius. This anatomical site is characterized by a thin cortical thickness that complicates traditional mechanical testing methods on specimens. Until now, mechanical properties of cortical bone at distal radius (e.g., elastic modulus, yield stress and strain) remain rarely studied probably due to experimental difficulties. The present study introduces an inverse finite-element method strategy to measure the elastic modulus and yield properties of human cortical specimens of the radial diaphysis. Twenty millimeter-thick portions of diaphysis were cut from 40 human radii (ages 45-90) for biomechanical test. Subsequently the same portion was modeled in order to obtain a specimen-specific three dimensional finite-element model (3D-FEM). Longitudinal elastic constants at the apparent level and stress characterizations were performed by coupling mechanical parameters with isotropic linear-elastic simulations. The results indicated that the mean apparent Young's modulus for radial cortical bone was 16 GPa (SD 1.8) and the yield stress was 153 MPa (SD 33). Breaking load was 12,946 N (SD 3644), cortical thickness 2.9 mm (SD 0.6), structural effective strain at the yield (epsilon(y)=0.0097) and failure (epsilon(u)=0.0154) load were also calculated. The 3D-FEM strategy described here may help to investigate bone mechanical properties when some difficulties arise from machining mechanical sample.     

Personalised Mechanical Properties of Scoliotic Vertebrae Determined In Vivo Using Tomodensitometry

This in vivo study investigated the mechanical properties of apical scoliotic vertebrae using computed tomography (CT) and finite element (FE) meshing. CT examination was performed on seven scoliotic girls. FE meshing of each vertebral body allowed automatic mapping of the CT scan and the visualisation of the bone density distribution. Centroids and mass centres were compared to analyse the mechanical properties distribution. Compared to the centroid, the mass centre migrated into the concavity of the curvature. The three vertebrae of a same patient had the same body migration behaviour because they were located at the curvature apex. This observation was verified in the coronal plane, but not in the sagittal plane. These results represent new data over few geometrical analyses of scoliotic vertebrae. Same in vivo personalisation of mechanical properties should be performed on intervertebral discs or ligaments to personalise stiffness properties of the spine for the biomechanical modelling of human torso. Moreover, do this mechanical deformation of scoliotic vertebrae, that appears before the vertebral wedging, could be a predictive tool in scoliosis treatment?     

Differences in vertebral structure and strength of inbred female mouse strains

This study assessed mouse strain-related differences in vertebral biomechanics and histomorphometry in inbred mice strains shown to differ in bone mineral content (BMC) and areal density (BMD) (as measured by pDEXA). Lumbar vertebrae L3 to L5 were collected from three mice strains (C3H/HeJ[C3], C57BL/6J[B6], and DBA/2J[D2], n=12/strain, 4-month-old female, 22.2 +/- 0.3g). BMC and BMD were measured in L3 and L4 using peripheral dual energy x-ray absorptiometry. The L4 vertebral body was then mechanically tested in compression to determine structural properties (ultimate/yield load, stiffness) from load-displacement curves and derive apparent material properties (ultimate/yield stress, and modulus of elasticity). L5 was processed for histomorphometric evaluation. Vertebral BMC and BMD were greater in C3 than in B6 and D2 mice. Vertebral trabecular/cancellous bone volume was smaller in C3 than in D2 and B6 mice. Trabecular bone formation rates were greater in D2 than in B6 and C3 mice. Osteoid surface was smaller in C3 mice than in B6 and D2 mice. Differences in osteoclast and mineralizing surfaces were not detected among the three mouse strains. In addition, there were no significant differences in biomechanical properties between the three strains. Despite the greatest BMC and areal BMD in C3 mice, the lack of strain-related differences in vertebral body strength data suggests that the biomechanical properties may be affected by the bone distribution and/or complex combination of cortical and cancellous bone at this site.     

Hindlimb unloading has a greater effect on cortical compared with cancellous bone in mature female rats.

This study was designed to determine the effects of 28 days of hindlimb unloading (HU) on the mature female rat skeleton. In vivo proximal tibia bone mineral density and geometry of HU and cage control (CC) rats were measured with peripheral quantitative computed tomography (pQCT) on days 0 and 28. Postmortem pQCT, histomorphometry, and mechanical testing were performed on tibiae and femora. After 28 days, HU animals had significantly higher daily food consumption (+39%) and lower serum estradiol levels (-49%, P = 0.079) compared with CC. Proximal tibia bone mineral content and cortical bone area significantly declined over 28 days in HU animals (-4.0 and 4.8%, respectively), whereas total and cancellous bone mineral densities were unchanged. HU animals had lower cortical bone formation rates and mineralizing surface at tibial midshaft, whereas differences in similar properties were not detected in cancellous bone of the distal femur. These results suggest that cortical bone, rather than cancellous bone, is more prominently affected by unloading in skeletally mature retired breeder female rats.     

Microdamage Caused by Fatigue Loading in Human Cancellous Bone: Relationship to Reductions in Bone Biomechanical Performance

Vertebral fractures associated with osteoporosis are often the result of tissue damage accumulated over time. Microscopic tissue damage (microdamage) generated in vivo is believed to be a mechanically relevant aspect of bone quality that may contribute to fracture risk. Although the presence of microdamage in bone tissue has been documented, the relationship between loading, microdamage accumulation and mechanical failure is not well understood. The aim of the current study was to determine how microdamage accumulates in human vertebral cancellous bone subjected to cyclic fatigue loading. Cancellous bone cores (n = 32) from the third lumbar vertebra of 16 donors (10 male, 6 female, age 76±8.8, mean ± SD) were subjected to compressive cyclic loading at σ/E₀ = 0.0035 (where σ is stress and E₀ is the initial Young’s modulus). Cyclic loading was suspended before failure at one of seven different amounts of loading and specimens were stained for microdamage using lead uranyl acetate. Damage volume fraction (DV/BV) varied from 0.8±0.5% (no loading) to 3.4±2.1% (fatigue-loaded to complete failure) and was linearly related to the reductions in Young’s modulus caused by fatigue loading (r² = 0.60, p<0.01). The relationship between reductions in Young’s modulus and proportion of fatigue life was nonlinear and suggests that most microdamage generation occurs late in fatigue loading, during the tertiary phase. Our results indicate that human vertebral cancellous bone tissue with a DV/BV of 1.5% is expected to have, on average, a Young’s modulus 31% lower than the same tissue without microdamage and is able to withstand 92% fewer cycles before failure than the same tissue without microdamage. Hence, even small amounts of microscopic tissue damage in human vertebral cancellous bone may have large effects on subsequent biomechanical performance.     

Apparent Young's modulus of vertebral cortico-cancellous bone specimens

Up to now, due to cortical thickness and imaging resolution, it is not possible to derive subject-specific mechanical properties on the 'vertebral shell' from imaging modalities applicable in vivo. As a first step, the goal of this study was to assess the apparent Young's modulus of vertebral cortico-cancellous bone specimens using an inverse method. A total of 22 cortico-cancellous specimens were harvested from 22 vertebral bodies. All specimens were tested in compression until failure. To compute the apparent Young's modulus of the specimen from the inverse method, the boundary conditions of the biomechanical experiments were faithfully reproduced in a finite element model (FEM), and an optimisation routine was used. The results showed a mean of the apparent Young's modulus of 374?±?208?MPa, ranging from 87 to 791?MPa. By computing an apparent Young's modulus of a cortico-cancellous medium, this study gives mechanical data for an FEM of an entire vertebra including an external shell combining both bone tissues.     

Material Changes in Osteoporotic Human Cancellous Bone Following Infiltration with Acrylic Bone Cement for a Vertebral Cement Augmentation

Bone cement infiltration can be effective at mechanically augmenting osteoporotic vertebrae. While most published literature describes the gain in mechanical strength of augmented vertebrae, we report the first measurements of viscoelastic material changes of cancellous bone due to cement infiltration. We infiltrated cancellous core specimen harvested from osteoporotic cadaveric spines with acrylic bone cement. Bone specimen before and after cement infiltration were subjected to identical quasi-static and relaxation loading in confined and free compression. Testing data were fitted to a linear viscoelastic model of compressible material and the model parameters for cement, native cancellous bone, and cancellous bone infiltrated (composite) with cement were identified. The fitting demonstrated that the linear viscoelastic model presented in this paper accurately describes the mechanical behaviour of cement and bone, before and after infiltration. Although the composite specimen did not completely adopt the properties of bulk bone cement, the stiffening of cancellous bone due to cement infiltration is considerable. The composite was, for example, 8.5 times stiffer than native bone. The local stiffening of cancellous bone in patients may alter the load transfer of the augmented motion segment and may be the cause of subsequent fractures in the vertebrae adjacent to the ones infiltrated with cement. The material model and parameters in this paper, together with an adequate finite-element model, can be helpful to investigate the load shift, the mechanism for subsequent fractures, and filling patterns for ideal cement infiltration.     

X-ray quantitative computed tomography: the relations to physical properties of proximal tibial trabecular bone specimens

Cylindrical bone specimens from the proximal epiphysis of ten normal human proximal tibiae were randomly assigned to a destructive axial compression test-series (N = 94) or to a protocol of standardized mechanical conditioning followed by non-destructive repeated testing to 0.6% strain and a final destructive test (N = 121). Specimen X-ray quantitative computed tomography (QCT) obtained at different scanning energies (100, 120 and 140 kVp) yielded closely related results (r = 1.00). Accordingly, predictions of physically measured densities or mechanical properties were not improved by using more than one scanning energy. QCT and physically measured densities were intimately related (QCT at 140 kVp to apparent density using linear regression: r = 0.94, and to apparent ash density: r = 0.95) and did not differ significantly in their ability to predict the mechanical properties, thus favouring the more easily implemented QCT for routine work. Evaluation of the relation of apparent density to Young's modulus and ultimate strength suggested that a power law regression model is preferable to a linear model, although linear model prediction of mechanical properties does not have significantly worse accuracy within the narrow density range investigated. The effect of conditioning on the behaviour of bone specimens subjected to destructive compression tests was to increase the stiffness and strength by approximately 50 and 20% respectively.     

Biomechanical allometry in hominoid thoracic vertebrae

Considerable differences in spinal morphology have been noted between humans and other hominoids. Although comparative analyses of the external morphology of vertebrae have been performed, much less is known regarding variations in internal morphology (density) and biomechanical performance among humans and closely related non-human primates. In the current study we utilize density calibrated computed tomography images of thoracic vertebral bodies from hominoids (n = 8-15 per species, human specimens 20-40 years of age) to obtain estimates of vertebral bone strength in axial compression and anteroposterior bending and to determine how estimates of strength scale with animal body mass. Our biomechanical analysis suggests that the strength of thoracic vertebral bodies is related to body mass (M) through power law relationships (y ∝ M^b) in which the exponent b is 0.89 (reduced major axis) for prediction of axial compressive strength and is equal to 1.89 (reduced major axis) for prediction of bending strength. No differences in the relationship between body mass and strength were observed among hominoids. However, thoracic vertebrae from humans were found to be disproportionately larger in terms of vertebral length (distance between cranial and caudal endplates) and overall vertebral body volume (p < 0.05). Additionally, vertebral bodies from humans were significantly less dense than in other hominoids (p < 0.05). We suggest that reduced density in human vertebral bodies is a result of a systemic increase in porosity of cancellous bone in humans, while increased vertebral body volume and length are a result of functional adaptation during growth resulting in a vertebral bone structure that is just as strong, relative to body mass, as in other hominoids.     

Characterization of bone-implant fixation using modal analysis: Application to a press-fit implant model

Orthopaedic implant fixation is strongly dependant upon the effective mechanical properties of newly formed tissue. In this study, we evaluated the potential of modal analysis to derive viscoelastic properties of periprosthetic tissue. We hypothesized that Young's modulus and loss factor could be obtained by a combined theoretical, computational and experimental modal analysis approach. This procedure was applied to ex vivo specimens from a cylindrical experimental implant placed in cancellous bone in an unloaded press-fit configuration, obtained after a four week observation period. Four sections each from seven textured titanium implants were investigated. The first resonant frequency and loss factor were measured. Average experimentally determined loss factor was 2% (SD 0.4%) and average first resonant frequency was 2.1 KHz (SD: 50). A 2D axisymmetric finite element (FE) model identified effective Young's modulus of tissue using experimental resonant frequencies as input. Average value was 42 MPa (SD: 2.4) and no significant difference between specimens was observed.In this pilot study, the non-destructive method allowed accurate measure of dynamic loss factor and resonant frequency and derivation of effective Young's modulus. Prior to implementing this dynamic protocol for broader mechanical evaluation of experimental implant fixation, further work is needed to determine if this affects results from subsequent destructive shear push-out tests.     

The mechanical behaviour of intracondylar cancellous bone of the femur at different loading rates

The compressive properties of human cancellous bone of the distal intracondylar femur in its wet condition were determined. Specimens were obtained from six cadaveric femora and were tested at a strain rate of 0.002, 0.10 and 9.16 sec⁻¹. It was found that the compressive strength decreases with an increasing vertical distance from the joint. The highest compressive strength level was recorded in the posterior medial condyle. Correlations among the mechanical properties, the bulk specimen density and the bone mineral content yield (i) highly significant correlations between the compressive strength and the elastic modulus (ii) highly significant correlations between the compressive strength or the modulus of elasticity and the bulk specimen density (iii) a doubtful correlation between the compressive strength and the bone mineral content. All recorded graphs of the impact loaded specimens displayed several well defined stress peaks, unlike the graphs recorded at low loading rates. It can be concluded that upon impact loading the localized trabecular failure which is associated with each peak, does not affect the spongy bone's stress capacity in a detrimental way.     

Post-yield relaxation behavior of bovine cancellous bone

Relaxation studies were conducted on specimens of bovine cancellous bone at post-yield strains. Stress and strain were measured for 1000 s and the relaxation modulus was determined. Fifteen cylindrical, cancellous bone specimens were removed from one bovine femur in the anterior–posterior direction. The relaxation modulus was found to be a function of strain. Therefore cancellous bone is non-linearly viscoelastic/viscoplastic in the plastic region. A power law regression was fit to the relaxation modulus data. The multiplicative constant was found to be statistically related through a power law relationship to both strain (p<0.0005) and apparent density (p<0.0005) while the power coefficient was found to be related through a power law relationship, E(t, ε)=A(ε)t^?n(ε), to strain (p<0.0005), but not apparent density.     

pQCT provides better prediction of canine femur breaking load than does DXA

Our study was designed to examine the validity of dual energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) measurements as predictors of whole bone breaking strength in beagle femora. DXA was used to determine the bone mineral content, bone area, and 'areal' bone mineral density. PQCT was used to determine the cross-sectional moments of inertia, volumetric densities of the bone, and to calculate bone strength indices based on bone geometry and density. A three-point bending mechanical test was used to determine maximal load. Three variables from the pQCT data set explained 88% of the variance in maximal load, with the volumetric bone mineral density explaining 32% of the variance. The addition of the volumetric cortical density increased the adjusted r(2) to 0.601 (p=0.001) and the addition of an index created by multiplying volumetric cortical bone density by the maximum cross-sectional moment of inertia made further significant (p<0.001) improvements to an adjusted r(2) of 0.877. In comparison, when only the DXA variables were considered in a multiple regression model, areal bone mineral density was the only variable entered and explained only 51% (p<0.001) of the variance in maximal load. These results suggest that pQCT can better predict maximal load in whole beagle femora since pQCT provides information on the bone's architecture in addition to its volumetric density.     

Dependence of mechanical properties of trabecular bone on plate–rod microstructure determined by individual trabecula segmentation (ITS)

Individual trabecula segmentation (ITS) technique can decompose the trabecular bone network into individual trabecular plates and rods and is capable of quantifying the plate/rod-related microstructural characteristics of trabecular bone. This novel technique has been shown to be able to provide in-depth insights into micromechanics and failure mechanisms of human trabecular bone, as well as to distinguish the fracture status independent of area bone mineral density in clinical applications. However, the plate/rod microstructural parameters from ITS have never been correlated to experimentally determined mechanical properties of human trabecular bone. In this study, on-axis cylindrical trabecular bone samples from human proximal tibia (n=22), vertebral body (n=10), and proximal femur (n=21) were harvested, prepared, scanned using micro computed-tomography (µCT), analyzed with ITS and mechanically tested. Regression analyses showed that the plate bone volume fraction (pBV/TV) and axial bone volume fraction (aBV/TV) calculated by ITS analysis correlated the best with elastic modulus (R²=0.96–0.97) and yield strength (R²=0.95–0.96). Trabecular plate-related microstructural parameters correlated highly with elastic modulus and yield strength, while most rod-related parameters were found inversely and only moderately correlated with the mechanical properties. In addition, ITS analysis also identified that trabecular bone at human femoral neck had the highest trabecular plate-related parameters while the other sites were similar with each other in terms of plate–rod microstructure.     

Correlations between indentation modulus and mineral density in bone-fracture calluses

The mechanical properties of a healing bone fracture depend not only on the geometry of the fracture callus but also on the material properties of the callus tissues. Despite the biomechanical importance of callus tissues in restoring mechanical integrity to the injured bone, little is known about the material properties of these tissues and whether these properties can be estimated non-invasively. This study used nanoindentation to quantify the spatial variations in indentation modulus throughout the fracture callus and correlated the measurements of modulus with measurements of tissue mineral density (TMD) obtained from images from micro-computed tomography (μCT). Fracture calluses were harvested from rats 24 days following creation of a full-thickness, transverse osteotomy in the femoral mid-diaphysis. Calluses were imaged using μCT, and the average TMD and the median grayvalue (X-ray attenuation) of five, pre-defined volumes of interest (VOIs) in each callus were computed. Nanoindentation was then performed at multiple, regularly spaced locations across 150 μm-thick, sagittal sections of the calluses. The indentation modulus ranged from 0.51 to 1680 MPa throughout the callus, with the highest moduli in the center of the fracture gap and the lowest in the periphery of the gap (P < 0.05). TMD was also highest in the center of the gap (P < 0.05). An increasing trend in both modulus and TMD was observed in the regions of the callus adjacent to the periosteal surfaces of the cortex. While no correlation was found between the average indentation modulus in a given VOI and the median grayvalue of that VOI, the average indentation modulus and the average TMD were positively correlated (R = 0.70, P < 0.05). Together, these findings establish the spatial heterogeneity in the mechanical behavior of tissues in fracture calluses and indicate that the indentation modulus of these tissues can be estimated by non-invasive measurements of tissue mineralization.     

Mechanical Properties of Black Locust (Robinia pseudoacacia) Wood: Correlations among Elastic and Rupture Moduli,Proportional Limit,and Tissue Density and Specific Gravity

The purpose of this paper is to determine the extent to which the physical and mechanical properties of dry and green wood samples are correlated. Samples of green (fresh) sap- and heartwood differing in density (ρ) were removed from the trunk of a black locust (Robinia pseudoacaciaL.) tree 30 years old and measuring 15 m in height. These samples were mechanically tested to determine their Young's elastic modulus (E), proportional (elastic) limit (σ_p), and modulus of rupture (σ_R). The Young's elastic modulus of green wood samples increased in magnitude to a limit with increasing cross-sectional area of the sample tested. The values of all three mechanical parameters measured for sapwood samples were consistently lower than those measured for heartwood samples with equivalent cross-sectional areas.Ewas linearly and positively correlated with the σ_pand σ_Rof heartwood tissue samples. All mechanical properties were highly correlated with the density of green heartwood. Likewise, these properties were highly correlated with the specific gravity of wood samples. Based on these results, it is concluded that either the density of fresh wood or the specific gravity of air-dried wood can be used to estimate the mechanical properties of black locust wood based on simple regression curves in the absence of extensive mechanical tests.     

Cell stiffness determined by atomic force microscopy and its correlation with cell motility

BackgroundCell stiffness is a crucial mechanical property that is closely related to cell motility. AFM is the most prevalent method used to determine cell stiffness by the quantitative parameter designated as Young's modulus. Young's modulus is regarded as a biomarker of cell motility, especially in estimating the metastasis of cancer cells, because in recent years, it has been repeatedly shown that cancerous cells are softer than their benign counterparts. However, some conflicting evidence has shown that cells with higher motility are sometimes stiffer than their counterparts. Thus, the correlation between cell stiffness and motility remains a matter of debate.Scope of reviewIn this review, we first summarize the reports on correlations between cell motility and stiffness determined by AFM and then discuss the major determinants of AFM-determined cell stiffness with a focus on the cytoskeleton, nuclear stiffness and methodological issues. Last, we propose a possible correlation between cell stiffness and motility and the possible explanations for the conflicting evidence.Major conclusionsThe AFM-determined Young's modulus is greatly affected by the characteristics of the cytoskeleton, as well as the procedures and parameters used in detection. Young's modulus is a reliable biomarker for the characterization of metastasis; however, reliability is questioned in the evaluation of pharmacologically or genetically modified motility.General significanceThis review provides an overview of the current understanding of the correlation between AFM-determined cell stiffness and motility, the determinants of this detecting method, as well as clues to optimize detecting parameters.