Remodeling Stimulus Research Articles

Load transfer in bone after partial, multi-compartmental, and total knee arthroplasty.

Introduction: Arthroplasty-associated bone loss remains a clinical problem: stiff metallic implants disrupt load transfer to bone and, hence, its remodeling stimulus. The aim of this research was to analyze how load transfer to bone is affected by different forms of knee arthroplasty: isolated partial knee arthroplasty (PKA), compartmental arthroplasty [combined partial knee arthroplasty (CPKA), two or more PKAs in the same knee], and total knee arthroplasty (TKA). Methods: An experimentally validated subject-specific finite element model was analyzed native and with medial unicondylar, lateral unicondylar, patellofemoral, bi-unicondylar, medial bicompartmental, lateral bicompartmental, tricompartmental, and total knee arthroplasty. Three load cases were simulated for each: gait, stair ascent, and sit-to-stand. Strain shielding and overstraining were calculated from the differences between the native and implanted states. Results: For gait, the TKA femoral component led to mean strain shielding (30%) more than three times higher than that of PKA (4%-7%) and CPKA (5%-8%). Overstraining was predicted in the proximal tibia (TKA 21%; PKA/CPKA 0%-6%). The variance in the distribution for TKA was an order of magnitude greater than for PKA/CPKA, indicating less physiological load transfer. Only the TKA-implanted femur was sensitive to the load case: for stair ascent and gait, almost the entire distal femur was strain-shielded, whereas during sit-to-stand, the posterior femoral condyles were overstrained. Discussion: TKA requires more bone resection than PKA and CPKA. These finite element analyses suggest that a longer-term benefit for bone is probable as partial and multi-compartmental knee procedures lead to more natural load transfer compared to TKA. High-flexion activity following TKA may be protective of posterior condyle bone resorption, which may help explain why bone loss affects some patients more than others. The male and female bone models used for this research are provided open access to facilitate future research elsewhere.

A comparative study of bone remodeling around hydroxyapatite-coated and novel radial functionally graded dental implants using finite element simulation

This comparative study simulates bone remodeling outcome around titanium dental implants and compares the final bone configuration with the one around novel implants composed of radial functionally graded materials (FGMs) and the titanium implants with hydroxyapatite (HA) coating. A dental implant system embedded in 3D mandibular bone with masticatory loading was simulated by the finite element method. A bone remodeling algorithm was applied to cancellous and cortical bones. Young's modulus and von Mises stress were obtained to ensure bone homeostasis and evaluate the final bone configuration. Local stress distribution in the bone-implant interface was analyzed before and after bone remodeling. The average final Young's modulus of cancellous bone reached 2.68, 2.49, and 2.32 GPa for the FGM, HA-coated, and the titanium models, respectively. These values for cortical bone were 17.75, 16.86, and 17.20 GPa in the same order. Radial FGM implants generated the highest remodeling stimulus and bone density. Their superiority over the HA-coated models was confirmed by four implant surface stiffness values (10, 20, 30, and 40 GPa). Remodeling increased bone density around the implant, consistent with clinical data and reduced stress concentration in the cortical neck. The stress values were in the safe zone regarding overload-induced bone resorption. The findings of this study were substantiated by clinical images and bone density values from previous literature.

Probing tissue transglutaminase mediated vascular smooth muscle cell aging using a novel transamidation-deficient Tgm2-C277S mouse model

Tissue transglutaminase (TG2), a multifunctional protein of the transglutaminase family, has putative transamidation-independent functions in aging-associated vascular stiffening and dysfunction. Developing preclinical models will be critical to fully understand the physiologic relevance of TG2’s transamidation-independent activity and to identify the specific function of TG2 for therapeutic targeting. Therefore, in this study, we harnessed CRISPR-Cas9 gene editing technology to introduce a mutation at cysteine 277 in the active site of the mouse Tgm2 gene. Heterozygous and homozygous Tgm2-C277S mice were phenotypically normal and were born at the expected Mendelian frequency. TG2 protein was ubiquitously expressed in the Tgm2-C277S mice at levels similar to those of wild-type (WT) mice. In the Tgm2-C277S mice, TG2 transglutaminase function was successfully obliterated, but the transamidation-independent functions ascribed to GTP, fibronectin, and integrin binding were preserved. In vitro, a remodeling stimulus led to the significant loss of vascular compliance in WT mice, but not in the Tgm2-C277S or TG2−/− mice. Vascular stiffness increased with age in WT mice, as measured by pulse-wave velocity and tensile testing. Tgm2-C277S mice were protected from age-associated vascular stiffening, and TG2 knockout yielded further protection. Together, these studies show that TG2 contributes significantly to overall vascular modulus and vasoreactivity independent of its transamidation function, but that transamidation activity is a significant cause of vascular matrix stiffening during aging. Finally, the Tgm2-C277S mice can be used for in vivo studies to explore the transamidation-independent roles of TG2 in physiology and pathophysiology.

Infraphysiological 17β-estradiol (E2) concentration compromises osteoblast differentiation through Src stimulation of cell proliferation and ECM remodeling stimulus

It has been shown that 17β-estradiol (E2) helps to prevent bone loss. This study was undertaken to verify whether E2 action in human osteoblasts involves changes in the transcriptional profile of the TNF-α, IFN-γ, NF-κB, TRAIL, TGF-β, MMP2, MMP9, RECK, TIMP1, TIMP2, CDK2, CDK4, SRC, RUNX2, and SHH genes. Infraphysiological doses of E2 elevated mRNAs in all genes except for INF-γ, TRAIL, and TGF-β. Importantly, a significant increase in the CDKs −2 and −4 genes was found, which strongly suggests cell cycle progression, with a potential dependency of Src involvement, as well as a suppression of the osteoblast differentiation machinery, with ECM remodeling being involved. These data suggest that E2 plays an important role in bone formation and remodeling, and Src seems to play a pivotal role in driving cell proliferation and ECM remodeling. Taken together, these findings contribute to an understanding of the effects of infraphysiological E2 on modulating bone homeostasis, favoring bone resorption, and leading to osteoporosis.

The interplay between bone healing and remodeling around dental implants

Long-term bone healing/adaptation after a dental implant treatment starts with diffusion of mesenchymal stem cells to the wounded region and their subsequent differentiation. The healing phase is followed by the bone-remodeling phase. In this work, a mechano-regulatory cellular differentiation model was used to simulate tissue healing around an immediately loaded dental implant. All tissue types were modeled as poroelastic in the healing phase. Material properties of the healing region were updated after each loading cycle for 30 cycles (days). The tissue distribution in the healed state was then used as the initial condition for the remodeling phase during which regions healed into bone adapt their apparent density with respect to a homeostatic remodeling stimulus. The short- (bone healing) and long-term (bone remodeling) effects of initial implant micromotion during the healing phase were studied. Development of soft tissue was observed both in the coronal region due to high fluid velocity, and on the vertical sides of the healing-gap due to high shear stress. In cases with small implant micromotion, tissue between the implant threads differentiated into bone during the healing phase but resorbed during remodeling. In cases with large implant micromotion, higher percentage of the healing region differentiated into soft tissue resulting in smaller volume of bone tissue available for remodeling. However, the remaining bone region developed higher density bone tissue. It was concluded that an optimal range of initial implant micromotion could be designed for a specific patient in order to achieve the desired long-term functional properties.

WOMEN’S FEMORAL MASS CONTENT CORRELATES TO MUSCLE STRENGTH INDEPENDENTLY OF LEAN BODY MASS

ABSTRACT Introduction There is limited consensus regarding the recommendation of the most effective form of exercise for bone integrity, despite the fact that weight training exercise promotes an increase in muscle mass and strength as recurrent responses. However, strength variations in women do not depend on muscle mass development as they do in men, but strength enhancement has shown the potential to alter bone mineral content (BMC) for both sexes. Objective This study analyzed the potential of muscle strength, as well as that of whole-body and regional body composition, to associate femoral BMC in young women. Methods Fifteen female college students (aged 24.9 ± 7.2 years) were assessed for regional and whole-body composition using dual-energy X-ray absorptiometry (DXA). Maximum muscle strength was assessed by the one-repetition maximum (1RM) test in the following exercises: bench press (BP), lat pulldown (LP), knee flexion (KF), knee extension (KE) and 45° leg press (45LP). Linear regression analyzed BMC relationships with regional composition and 1RM values. Dispersion and error measures (R 2 aj and SEE), were tested, defining p ≤0.05. Results Among body composition variables, only total lean body mass was associated with femoral BMC values (R 2 aj = 0.37, SEE = 21.3 g). Regarding strength values, 1RM presented determination potential on femoral BMC in the CE exercise (R 2 aj = 0.46, SEE = 21.3 g). Conclusions Muscle strength aptitude in exercises for femoral regions is relevant to the femoral mineralization status, having associative potential that is similar to and independent of whole-body lean mass. Therefore, training routines to increase muscle strength in the femoral region are recommended. In addition, increasing muscle strength in different parts of the body may augment bone remodeling stimulus, since it can effectively alter total whole-body lean mass. Level of Evidence II; Development of diagnostic criteria in consecutive patients (with universally applied reference ‘‘gold’’ standard).

Fibroblast-secreted trophic factors contribute with ECM remodeling stimulus and upmodulate osteocyte gene markers in osteoblasts

As osteogenesis is a multifactorial mechanism, we wonder whether osteoblast-induced extracellular matrix (ECM) remodeling might be modulated by trophic factors released by fibroblasts in a paracrine signaling manner. To address this issue, fibroblasts were cultured for 72 h under conventional conditions when their conditioned medium was harvested and used to challenge pre-osteoblasts (MC3T3-E1 cells) for 14 days. Preliminarily, we validated the potential effect of fibroblasts in contributing to osteocyte phenotype, which specifically requires significant expression of Dentin Matrix Protein 1 (DMP1; about 10-fold changes) and Sclerostin (SOST; about 7-fold changes), both biomarkers of osteocyte. Fibroblasts also seem contributing to ECM remodeling in osteoblasts, because we detected a high level of both mRNA and enzyme activities of matrix metalloproteinase −9 (MMP-9) as well as a high level of reversion inducing cysteine rich protein with kazal motifs (RECK) transcripts (about 13-fold changes), a membrane-anchored MMP inhibitor, which seems to be a constitutive pathway in osteoblasts. Considering inflammatory panorama and using RTqPCR technology, both IL-13 (about 13-fold changes) and IL-33 (about 5-fold changes) genes were up-expressed in response to the fibroblast-secreted trophic factors, as were the receptor activator of NF-κB ligand (RANKL; about 8-fold changes) and osteoprotegerin (OPG; about 3-fold changes). Although preliminary, these data suggest a stimulus to finely control osteoclastogenesis, and this mechanism reinforces the role of fibroblasts in bone remodeling and homeostasis. Moreover, these results suggest an important crosstalk between fibroblast and osteoblast, when fibroblast-secreted trophic factors upmodulate osteocyte gene markers and contribute to ECM remodeling stimulus in osteoblast.

Capturing microscopic features of bone remodeling into a macroscopic model based on biological rationales of bone adaptation.

To understand Wolff's law, bone adaptation by remodeling at the cellular and tissue levels has been discussed extensively through experimental and simulation studies. For the clinical application of a bone remodeling simulation, it is significant to establish a macroscopic model that incorporates clarified microscopic mechanisms. In this study, we proposed novel macroscopic models based on the microscopic mechanism of osteocytic mechanosensing, in which the flow of fluid in the lacuno-canalicular porosity generated by fluid pressure gradients plays an important role, and theoretically evaluated the proposed models, taking biological rationales of bone adaptation into account. The proposed models were categorized into two groups according to whether the remodeling equilibrium state was defined globally or locally, i.e., the global or local uniformity models. Each remodeling stimulus in the proposed models was quantitatively evaluated through image-based finite element analyses of a swine cancellous bone, according to two introduced criteria associated with the trabecular volume and orientation at remodeling equilibrium based on biological rationales. The evaluation suggested that nonuniformity of the mean stress gradient in the local uniformity model, one of the proposed stimuli, has high validity. Furthermore, the adaptive potential of each stimulus was discussed based on spatial distribution of a remodeling stimulus on the trabecular surface. The theoretical consideration of a remodeling stimulus based on biological rationales of bone adaptation would contribute to the establishment of a clinically applicable and reliable simulation model of bone remodeling.

Finite Element Simulation of Implant Placement following Extraction of a Single Tooth

The aim of the study was to assess some possible factors influencing the bone stresses and remodeling process after the placement of an implant in a postextraction socket. A finite element model of a portion of the maxilla was used. Three osseointegrated titanium dental implants with different thread profiles were placed into the extraction socket. Three different lengths, thus with different depth into the bone, were considered. Bone remodeling was simulated by using the strain energy density as the remodeling stimulus. A load with magnitude 200 N and inclination of 45° to the longitudinal axis in the lateral direction was applied directly to the implant. Both implant length and thread profile had an influence on the bone stresses, growth and loss after implantation. Longer implants reduced both the size of the bone loss area and the total bone mass loss. It is not easy to establish the relationship of the long-term success of implantation and bone turnover activity via clinical trials. After a proper clinical validation, the protocol developed using computational modeling may become a viable option to predict the clinical outcome, even on a patient-specific basis, regarding its noninvasive and time-efficient nature.

Collateral Expansion and Capillary Arterialization in the Spinotrapezius of C57BL/6, BALB/c and NG2 Knockout Mice

Recent work from our lab and other groups has indicated that inherent differences in microvascular architecture between mouse strains may be the underlying cause of variation in collateral expansion and capillary arterialization following a remodeling stimulus. We sought to examine these differences in C57BL/6 and BALB/c mice, strains with many and few/no collateral arteriolar connections, respectively, following ischemic ligation in the spinotrapezius muscle. In BALB/c mice, the percentage of actin-positive capillaries increased 190% seven days after ischemic ligation compared to controls, returning to near-control levels by 21 days. The total length of actin-positive vessels increased 52% seven days after ligation compared to controls, and was sustained out to 21 days. Ligated BALB/c muscles exhibit a 56% increase in small-arteriole length density seven days following treatment when compared to controls which was again sustained for 21 days. In C57BL/6 mice, ligated muscles had a 37% increase in large-arteriole length density 21 days after treatment compared to controls. No significant changes in capillary length density were observed following seven or 21 days of whole-body hypoxia in either strain. These results suggest that the presence or absence of arteriolar collateral connections influences the location and type of microvascular remodeling that occurs in the mouse spinotrapezius.

The Restoration of Lumbar Intervertebral Disc Load Distribution

A validated L3-L4 nonlinear finite element model was used to evaluate strain and pressure in the surrounding structures for 4 nucleus replacement technologies. The objective of the current study was to compare subsidence and anular damage potential between 4 current nucleus replacement technologies. It was hypothesized that a fully conforming nucleus replacement would minimize the risk of both subsidence and anular damage. Nucleus pulposus replacements are emerging as a less invasive alternative to total disc replacement and fusion as a solution to degenerative intervertebral discs. Multiple technologies have been developed and are currently undergoing clinical investigation. The testing conditions were applied by excavating the nucleus of the intact model and virtually implanting models representing the various nucleus replacement technologies. The implants consisted of a conforming injectable polyurethane (E = 4 MPa), soft hydrogel (E = 4 MPa), stiff hydrogel (E = 20 MPa), and polyether-etherketone (PEEK) on PEEK articulating designs. The model was exercised in flexion, extension, lateral bending, axial rotation (7.5 Nm with 450 N preload), and compression (1000 N). Vertebral body strain, anular maximum shear strain, endplate contact pressure, anulus-implant contact pressure, and bone remodeling stimulus were reported. The PEEK implant induced strain maxima in the vertebral bodies with associated endplate contact pressure concentrations. For the PEEK and hydrogel implants, areas of nonconformity with the endplate indicated adjacent bone resorption. Lack of conformity between the implant and inner anulus for the PEEK and hydrogel implants resulted in inward anular bulging with associated increased maximum shear strain. The conforming polyurethane implant maintained outward bulging of the inner anular wall and indicated no bone resorption or stress shielding adjacent to the implant. A fully conforming nucleus replacement resulted in a decreased propensity for subsidence, anular bulging, and further degeneration of the anulus when compared with nonconforming implants.

Effect of Nucleus Replacement Device Properties on Lumbar Spine Mechanics

A validated nonlinear three-dimensional finite element model of a single lumbar motion segment (L3-L4) was used to evaluate a range of moduli for ideally conforming nucleus replacement devices. The objective of the current study was to determine the biomechanical effects of nucleus replacement technology for a variety of implant moduli. We hypothesized that there would be an optimal modulus for a nucleus replacement that would provide loading in the surrounding bone and anulus similar to the intact state. Nucleus pulposus replacements are interventional therapies that restore stiffness and height to mildly degenerated intervertebral discs. Currently a wide variety of nucleus replacement technologies with a large range of mechanical properties are undergoing preclinical testing. A finite element model of L3-L4 was created and validated using range of motion, disc pressure, and bony strains from previously published data. The intact model was altered by changing the mechanical properties of the nucleus pulposus to represent a wide range of nucleus replacement technologies (E = 0.1, 1, 4, and 100 MPa). All of the models were exercised in compression, flexion, extension, lateral bending, and axial rotation. Vertebral body strain, peak anulus fibrosus shear strain, initial bone remodeling stimulus, range of motion, and center of rotation were analyzed. A nucleus replacement modulus of 1 and 4 MPa resulted in vertebral body strains similar to the intact model. The softest device indicated increased loading in the AF and bone resorption adjacent to the implant. Areas of strain maxima and bone formation were observed adjacent to the implant for the stiffest device. The current study predicted an optimal nucleus replacement of 1 to 4 MPa. An overly stiff implant could result in subsidence, which would preclude the benefit of disc height increase or restoration. Conversely, an overly soft implant could accelerate a degenerative cascade in the anulus.

Genomic Analysis of Left Ventricular Remodeling

The left ventricle (LV) of the heart remodels in response to hemodynamic load through the processes of physiological or pathophysiological hypertrophy.1–3 Despite extensive study of the molecular basis of cardiac hypertrophy and LV remodeling,1,4 the mainstay of medical treatment of maladaptive remodeling remains based on therapies initially devised for treating hypertension. The limited progress in the development of specific therapies for LV remodeling has led some to refer to “the impossible task of developing a new treatment for heart failure” and is the reason why, in part, device therapies have received such recent attention.5–8 To gain a better understanding of the biology of maladaptive LV remodeling, with a view to identifying therapeutic targets, new paradigms and experimental approaches are needed, and genomics provides one such methodology. Genomics is the study of genome-scale data sets, at the DNA or RNA level, and when combined with studies of physiological traits or disease phenotypes, genomics can be used to infer molecular insights. Unlike single-gene studies, which are the favored hypothesis-driven design,4 genomic approaches examine variation in up to gigabases of sequences to find statistical associations between transcripts and traits in a hypothesis-free system. These hypothesis-free studies have often been criticized as unfocused, but following the successes of genome-wide association studies (GWAS) and the recent achievements of integrated genetic and genomic analyses, a new era of genomic experimentation presents itself.9–14 It is notable that GWAS and integrated genomic studies in humans often identify regions associated with disease rather than specific genes and that effect sizes are small; nevertheless, these data remain highly informative.15–17 In this article, we review the genomic analysis of LV remodeling in the context of the recent past, the state of the art, and the imminent use of next-generation sequencing. A glossary of terms is …

Role of Surgical Position on Interface Stress and Initial Bone Remodeling Stimulus around Hip Resurfacing Arthroplasty

Valgus alignment of femoral resurfacing components has been advocated to reduce proximal femur loading and thus minimize the risk for femoral neck fractures. However, such reduction in loading may exacerbate undesirable stress shielding. This study examined the effect of extreme implant orientations (±15°) and stem canal overreaming on initial bone remodeling stimulus using finite element models. The changes in implant-cement interface stresses due to implant alignment were also evaluated. The valgus model showed increased initial bone resorption stimulus, which extended distally and peripherally around the femoral neck. The peak implant-cement interface shear stress for the varus model was 10.9 MPa, exceeding the interface shear strength. Overreaming of the stem canal eliminated distal tip loading, but proximal stress shielding was still unavoidable. These data show bone loading and interface fixation trends emanating from valgus and varus implant positions that will be of interest to practicing physicians.

Osteal Tissue Macrophages Are Intercalated throughout Human and Mouse Bone Lining Tissues and Regulate Osteoblast Function In Vitro and In Vivo

Resident macrophages are an integral component of many tissues and are important in homeostasis and repair. This study examines the contribution of resident tissue macrophages to bone physiology. Using immunohistochemistry, we showed that a discrete population of resident macrophages, OsteoMacs, was intercalated throughout murine and human osteal tissues. OsteoMacs were distributed among other bone lining cells within both endosteum and periosteum. Furthermore, OsteoMacs were coisolated with osteoblasts in murine bone explant and calvarial preparations. OsteoMacs made up 15.9% of calvarial preparations and persisted throughout standard osteoblast differentiation cultures. Contrary to previous studies, we showed that it was OsteoMacs and not osteoblasts within these preparations that responded to pathophysiological concentrations of LPS by secreting TNF. Removal of OsteoMacs from calvarial cultures significantly decreased osteocalcin mRNA induction and osteoblast mineralization in vitro. In a Transwell coculture system of enriched osteoblasts and macrophages, we demonstrated that macrophages were required for efficient osteoblast mineralization in response to the physiological remodeling stimulus, elevated extracellular calcium. Notably, OsteoMacs were closely associated with areas of bone modeling in situ, forming a distinctive canopy structure covering >75% of mature osteoblasts on diaphyseal endosteal surfaces in young growing mice. Depletion of OsteoMacs in vivo using the macrophage-Fas-induced apoptosis (MAFIA) mouse caused complete loss of osteoblast bone-forming surface at this modeling site. Overall, we have demonstrated that OsteoMacs are an integral component of bone tissues and play a novel role in bone homeostasis through regulating osteoblast function. These observations implicate OsteoMacs, in addition to osteoclasts and osteoblasts, as principal participants in bone dynamics.

PRESSURE‐ AND FLOW‐DEPENDENT VASCULAR REMODELING IN MICE DEFICIENT FOR TISSUE‐TYPE TRANSGLUTAMINASE

Tissue-type transglutaminase (tTG) acts as a biological glue by cross-linking extracellular matrix proteins. We tested whether tTG plays a role in the remodeling of small arteries in hypertension and reduced blood flow. Mice were given L-NAME to induce hypertension. Blood pressure increased similarly in wild type (WT) and tTG null mice (119 ± 3 to 144 ± 4 mmHg vs. 115 ± 3 to 137 ± 5 mmHg). After one week, mesenteric arteries were isolated and pressure-diameter relationships were determined in vitro under fully dilated conditions. WT mice showed inward remodeling (−10%), whereas tTG null mice did not (+3%), expressed as difference in lumen diameter at 80 mmHg. In the second series of experiments, blood flow was modified in mesenteric arteries by a surgical intervention. Two days after a reduction in blood flow arteries of WT mice showed inward remodeling (−17 ± 3%) while vessels from tTG null mice did not (0 ± 2%). However, after 7 days inward remodeling in WT and tTG null mice was similar: −18 ± 1% vs. −21 ± 2%. While tTG null mice lacked tTG expression, arteries did show the cross-link specific for transglutaminases. RT-PCR revealed the expression of type 1 transglutaminase and the plasma transglutaminase, Factor XIII in both WT and tTG null mice. These data show that tTG plays a crucial role in the inward remodeling of small arteries in both hypertension and reduced blood flow. Other transglutaminases are expressed but do not fully compensate when arteries are challenged with a remodeling stimulus. Supported by the Netherlands Heart Foundation (NHS 2001.D038).

Simulation Study on Local and Integral Mechanical Quantities at Single Trabecular Level as Candidates of Remodeling Stimuli

Mechanical quantities at the microstructural level play important roles as stimuli of trabecular bone remodeling by which cancellous bone maintains and adapts its trabecular structure to the mechanical environment. In this study, distribution functions of mechanical quantities on trabecular surfaces were estimated using digital image-based finite element models of five specimens of rat vertebral bodies under physiological loading conditions. As the representative quantities that have been used as mechanical stimuli in the remodeling rate equation, strain energy density (SED) and von Mises equivalent stress were considered for the mechanical quantities at the local point (namely, local mechanical quantities), and SED integration and stress nonuniformity were considered for the quantities that are integrated in space (namely, integral mechanical quantities). As a result of finite element analysis, it was demonstrated that these mechanical quantities were nonuniformly distributed over the trabecular surface due to the three-dimensionally complicated trabecular structure, even though only simple external loading was applied to the vertebral body. The magnitude of the skewness of the distribution function was calculated in order to compare the distribution patterns of the four mechanical quantities. The skewness for SED and equivalent stress in all the loading cases were larger than those for SED integration and stress nonuniformity, respectively, except that in the loading of axial compression, the skewness for equivalent stress was smaller than that for stress nonuniformity. It was also revealed that the skewness varied with changes in the external loading conditions, where changes in the mean and the standard deviation of the skewness for SED integration and stress nonuniformity were smaller than those for SED and equivalent stress. The results support the understanding that the concept of the integral formulae proposed for the bone remodeling stimulus corresponds not only to the actual biological system but also to the observed phenomenon of trabecular structural adaptation to the mechanical environment.

Damage in trabecular bone at small strains

Evidence that damage decreases bone quality, increases fracture susceptibility, and serves as a remodeling stimulus motivates further study of what loading magnitudes induce damage in trabecular bone. In particular, whether damage occurs at the smaller strains characteristic of habitual, as opposed to traumatic, loading is not known. The overall goal of this study was to characterize damage accumulation in trabecular bone at small strains (0.20 - 0.45% strain). A continuum damage mechanics approach was taken whereby damage was quantified by changes in modulus and residual strain. Human vertebral specimens (n = 7) were tested in compression using a multi-cycle load - unload protocol in which the maximum applied strain for each cycle, epsilonmax, was increased incrementally from epsilonmax = 0.20% on the first loading cycle to epsilonmax = 0.45% on the last cycle. Modulus and residual strain were measured for each cycle. Both changes in modulus and residual strains commenced at small strains, beginning as early as 0.24 and 0.20% strain, respectively. Strong correlations between changes in modulus and residual strains were observed (r = 0.51 - 0.98). Fully nonlinear, high-resolution finite element analyses indicated that even at small apparent strains, tissue-level strains were sufficiently high to cause local yielding. These results demonstrate that damage in trabecular bone occurs at apparent strains less than half the apparent compressive yield strain reported previously for human vertebral trabecular bone. Further, these findings imply that, as a consequence of the highly porous trabecular structure, tissue yielding can initiate at very low apparent strains and that this local failure has detectable and negative consequences on the apparent mechanical properties of trabecular bone.

Structural remodeling of mouse gracilis artery after chronic alteration in blood supply

The goals of this study were to determine the time course and spatial dependence of structural diameter changes in the mouse gracilis artery after a redistribution of blood flow and to compare the observations with predictions of computational models for structural adaptation. Diameters were measured 1, 2, 7, 14, 21, 28, and 56 days after resection of one of the two blood supplies to the artery. Overall average diameter, normalized with respect to diameters in untreated vessels, increased slightly during the first 7 days, then increased more rapidly, reaching a peak around day 21, and then decreased. This transient increase in diameter was spatially nonuniform, being largest toward the point of resection. A previously developed theoretical model, in which diameter varies in response to stimuli derived from local metabolic and hemodynamic conditions, was extended to include effects of time-delayed remodeling stimuli in regions of reduced perfusion. Predictions of this model were consistent with observed diameter changes, including the transient increase in diameters near the point of resection, when a remodeling stimulus with a time delay of approximately 7 days was included. The results suggest that delayed stimuli significantly influence the dynamic characteristics of vascular remodeling resulting from reduced blood supply.

Temporal events underlying arterial remodeling after chronic flow reduction in mice: correlation of structural changes with a deficit in basal nitric oxide synthesis.

To define the cellular events of vascular remodeling in mice, we measured blood flow and analyzed the morphology of remodeled vessels at defined points after a flow-reducing remodeling stimulus for 3, 7, 14, and 35 days. Acute ligation of the left external carotid artery reduced blood flow in the left common carotid artery (LC) compared with sham and contralateral right common carotid arteries (RCs). In morphometric analyses, the decrease in diameter in LCs was reversible by vasodilator perfusion 3 days after ligation, whereas ligation for 7 days or greater resulted in a permanent diameter reduction. Coincident with structural remodeling at day 7 was an increase in cell death in remodeled LCs. Functionally, rings from remodeled LCs contracted to prostaglandin F(2alpha) and relaxed to acetylcholine in a manner identical to that of control arteries. However, remodeled LCs were hypersensitive to the nitrovasodilator sodium nitroprusside (at day 7) and exhibited a marked reduction in basal NO synthesis at 7 and 14 days after ligation. The impairment of endothelial NO synthase function was likely due to post-translational mechanisms, given that endothelial NO synthase mRNA and protein levels did not change in remodeled LCs. These data define the ontogeny of flow-triggered luminal remodeling in adult mice and suggest that endothelial dysfunction occurs during reorganization of the vessel wall.