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PubMed2002

Glycated collagen cross-linking alters cardiac mechanics in volume-overload hypertrophy.

Alteration of hemodynamic loading induces remodeling that includes changes in myocardial properties and extracellular matrix structure. We investigated the hypothesis that cardiac hypertrophy due to volume overload produces changes in myocardial diastolic mechanics and stiffness that are in part due to alterations in advanced glycation end-product (AGE) collagen cross-linking. Rats developed volume overload induced by arteriovenous fistula (AVF). To assess the dependence of AGE cross-linking on mechanics, we prevented AGE formation by administering the drug aminoguanidine (AG) to one group of AVF rats (AG+AVF). Volume overload did not modify collagen concentration. Right ventricular AGE cross-links were modestly elevated in AVF hearts but were significantly reduced by AG. AVF rats exhibited significantly increased septal AGE cross-links that were inhibited in the AG+AVF group. AVF-induced increases in left ventricular longitudinal stiffness and septal circumferential stiffness were prevented in AG+AVF hearts. Volume overload appears to regionally modify AGE collagen cross-linking and stiffness, and AG treatment prevented these increases, demonstrating that AGE cross-linking plays a role in mediating diastolic compliance in volume-overload hypertrophy.

Animals↗
PubMed2002

The role of fibril reinforcement in the mechanical behavior of cartilage.

Collagen fibril reinforcement was incorporated into a nonlinear poroelastic model for articular cartilage in unconfined compression. It was found that the radial fibrils play a predominant role in the transient mechanical behavior but a less important role in the equilibrium response of cartilage. The radial fibrils are in tension and can be highly stressed during compression, in contrast to low compressive stresses in all directions for the proteoglycan matrix after a small initial compression. The strain dependent fibril stiffening produces strong nonlinear transient response; the fibrils provide extra stiffness to balance a rising fluid pressure and to restrain stress increase in the proteoglycans. The fibril reinforcement, induced by the fluid pressure and flow, also accounts for a complex pattern of strain-magnitude and strain-rate dependence of cartilage stiffness.

Animals↗
PubMed2006

Oxidative mechanism and homeostasis of proteinase/antiproteinase in congestive heart failure.

Takenaka et al. [Takenaka H, Kihara Y, Iwanaga Y, Onozawa Y, Toyokuni S, Kita T. Angiotensin II, oxidative stress, and extracellular matrix degradation during transition to LV failure in rats with hypertension, J Mol Cell Cardiol, 2006; in press] in this issue have shown that during LV failure in hypertension, there is induction of oxidative stress in which p47 and gp91, and glutathione peroxidase are increased via the NFkB pathway oxidative stress which induces the MMP/TIMP axis, leading to cardiac dilation and failure. The ARB ameliorates the CHF by decreasing oxidative stress [Funabiki K, et al., Combined angiotensin receptor blocker and ACE inhibitor on myocardial fibrosis and LV stiffness in dogs with heart failure, Am J Physiol, 2004; 287(6): H2487-92]. This study supports the notion that the inciting oxidative stress activates the matrix degrading proteinase. That disrupts the connective tissue matrix homeostasis in between the myocyte and endothelial cells causing disruption in synchronization in cardiac systolic contraction and diastolic relaxation. The treatment with ARB mitigates this disruption in cardiac synchrony.

Angiotensin II↗
PubMed2005

An immunohistochemical study of the extracellular matrix of the tarsal plate in the upper eyelid in human beings.

The superior tarsus is a plate of tissue that stiffens the upper eyelid, gives it support and determines its form. The purpose of the present study was to relate the composition of its extracellular matrix to its function and to report regional differences that may influence the activity of its Meibomian glands. Fourteen methanol-fixed specimens were cryosectioned for immunohistochemistry and labelled with a panel of monoclonal antibodies against a wide range of collagens, glycosaminoglycans and proteoglycans. Labelling was detected with avidin-biotin-peroxidase. A further six specimens were formalin-fixed for routine histology. The tarsal plate immunolabelled strongly for types I, III and VI collagen and for aggrecan, versican, tenascin, cartilage oligomeric matrix protein (COMP) together with a variety of glycosaminoglycans (notably chondroitin 6 sulphate). A region of strong labelling for aggrecan, dermatan sulphate and chondroitin 6 sulphate immediately surrounded the Meibomian glands. The site of labelling corresponded to a layer of acellular and amorphous matrix seen histologically that we have termed the 'territorial matrix'. The results suggested that the tarsal plate is a specialized connective tissue that is neither purely fibrous nor cartilaginous, yet has an aggrecan content that probably contributes to its stiffness. Its unique character highlights the challenge in choosing an ideal mechanical substitute. As patients with rheumatoid arthritis often have problems relating to tear film deficiency, the ability of aggrecan or COMP to act as autoantigens may be significant. An immune reaction directed against these molecules could alter tarsal gland function by interfering with the interaction between the glands and their territorial matrix.

Adult↗
PubMed2003

Congenital lack of COX-2 affects mechanical and geometric properties of bone in mice.

We compared the mechanical properties of bones from mice lacking either a functional cycloxygenase-1 (C57BL6/DBA COX-1-/-; n = 9) or COX-2 (C57BL6/DBA COX-2-/-; n = 9) gene and wild type mice (C57BL6/DBA; n = 10). Twenty-eight right femora from 3-month-old male mice were used to determine bulk structural and material properties of bone by three-point bending. Bone matrix properties were also measured by nanoindentation to access the changes in bulk mechanical properties due to changes in bone matrix or bone geometry. The bulk material properties (elastic modulus, P < 0.05; ultimate stress, P < 0.01) of COX-2-/- bones were lower than those of wild-type mice whereas the bulk structural properties (stiffness, P > 0.2; breaking force, P > 0.1) were similar to those of the wild-type mice. COX-2-/- mice had a longer moment of inertia but their cortical bones were thinner and contained many more intra-cortical pores compared with the bones of the other two groups. Finally, the bone matrix properties of COX-1-/- mice, COX-2-/- mice and their heterozygous littermates were similar to those of C57BL6/DBA wild-type mice.

Animals↗
PubMed2001

Receptor-based differences in human aortic smooth muscle cell membrane stiffness.

Cells respond to mechanical stimuli with diverse molecular responses. The nature of the sensory mechanism involved in mechanotransduction is not known, but integrins may play an important role. The integrins are linked to both the cytoskeleton and extracellular matrix, suggesting that probing cells via integrins should yield different mechanical properties than probing cells via non-cytoskeleton-associated receptors. To test the hypothesis that the mechanical properties of a cell are dependent on the receptor on which the stress is applied, human aortic smooth muscle cells were plated, and magnetic beads, targeted either to the integrins via fibronectin or to the transferrin receptor by use of an IgG antibody, were attached to the cell surface. The resistance of the cell to deformation ("stiffness") was estimated by oscillating the magnetic beads at 1 Hz by use of single-pole magnetic tweezers at 2 different magnitudes. The ratio of bead displacements at different magnitudes was used to explore the mechanical properties of the cells. Cells stressed via the integrins required approximately 10-fold more force to obtain the same bead displacements as the cells stressed via the transferrin receptors. Cells stressed via integrins showed stiffening behavior as the force was increased, whereas this stiffening was significantly less for cells stressed via the transferrin receptor (P<0.001). Mechanical characteristics of vascular smooth muscle cells depend on the receptor by which the stress is applied, with integrin-based linkages demonstrating cell-stiffening behavior.

Antibodies↗
PubMed1989

Ageing of radiation-sterilized polypropylene: changes in semicrystallinity.

Studies on radiation sterilization of isotactic polypropylene intended for biomedical applications were carried out for uncovered and covered samples. The effect of ageing on these samples was studied by determining the changes in relative crystallinity. The semicrystalline nature of the polymer is responsible for the changes in crystallinity. The transitions between short- and long-range order and short- and long-duration stiffness in both covered and uncovered samples, reflected in changes in relative crystallinity, were highly affected by the formation of branches in the backbone of the polymer. The high degree of branching in covered samples resulted in greater long-duration stiffness in the transition between short- and long-duration stiffness. The high degree of branching in covered samples was attributed to the high diffusion of energized oxygen into the polymer matrix compared with uncovered samples. The changes in relative crystallinity were rapid in uncovered samples (70% max; 34% min) but rather slow in covered samples (87% max; 43% min).

Biocompatible Materials↗
PubMed2000

About composite materials and their use in bone surgery.

Composite materials consist of two or even more different material components or phases, which are combined with the aim to improve physical, mechanical and/or biological properties. Such structures are designed to fulfil very specific requirements with respect to a selected device application making full use of their higher weight-specific strength and/or stiffness. Furthermore, these materials offer an opportunity for constructing radiolucent devices. In medical technology, composite materials mainly consist of a polymer matrix and fibres as a reinforcement phase. Composites similar to those known from technical applications reveal a number of specific biological problems. This is due to the materials and manufacturing processes available for the construction of such composites preventing their unrestricted use in direct bone contact. Nevertheless, an application potential for these materials in bone surgery exists and justifies further research and development efforts.

Composite Resins↗
PubMed2005

COMP mutation screening as an aid for the clinical diagnosis and counselling of patients with a suspected diagnosis of pseudoachondroplasia or multiple epiphyseal dysplasia.

The skeletal dysplasias are a clinically and genetically heterogeneous group of conditions affecting the development of the osseous skeleton and fall into the category of rare genetic diseases in which the diagnosis can be difficult for the nonexpert. Two such diseases are pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED), which result in varying degrees of short stature, joint pain and stiffness and often resulting in early onset osteoarthritis. PSACH and some forms of MED result from mutations in the cartilage oligomeric matrix protein (COMP) gene and to aid the clinical diagnosis and counselling of patients with a suspected diagnosis of PSACH or MED, we developed an efficient and accurate molecular diagnostic service for the COMP gene. In a 36-month period, 100 families were screened for a mutation in COMP and we identified disease-causing mutations in 78% of PSACH families and 36% of MED families. Furthermore, in several of these families, the identification of a disease-causing mutation provided information that was immediately used to direct reproductive decision-making.

Adolescent↗
PubMed1997

Probing mechanical properties of living cells by magnetopneumography.

Magnetopneumography (MPG) has been used to study long-term particle clearance from human lungs as well as cellular motility of pulmonary macrophages (PMs). This study describes an extension of the method enabling the measurement of mechanical properties of PM cells in vivo. Ferromagnetic microparticles are inhaled and then retained in the alveolar region of the lungs, where they are phagocytized within hours by PMs. The magnetic particles can be rotated in weak magnetic fields, and the response to this twisting shear (force) is detected as a macroscopic magnetic field producing a measure of cytoskeletal mechanics. Cytoplasmic viscosity is very high compared with that of water and is strongly non-Newtonian. Under rotational stresses from 0.4 to 6.4 Pa, it acts like a pseudoplastic fluid showing a characteristic shear rate dependence. The viscosity as well as the stiffness of the cytoskeleton increases with increasing shear stress as seems typical for living tissue and evidence for an intact cytoskeletal matrix. The particle recoil as measured by the amount of recoverable strain following a short twisting force describes a cytoplasmic elasticity that depends on both level and duration of stress. These investigations on the mechanical properties of living human cells are promising and should lead to better understanding of cellular dysfunction in disease as well as pathways for drug administration.

Adult↗
PubMed1989

Myocardial collagen and mechanics after preventing hypertrophy in hypertensive rats.

To determine if a remodeling of the collagen matrix would occur in the absence of hypertrophy and cell necrosis and if such a remodeling could alter active and passive stiffness of the intact myocardium, five rats with genetic hypertension (SHR) were treated (SHRT) with hydralazine for 32 weeks, beginning at four weeks of age, and compared to six age- and sex-matched SHR and seven Wistar-Kyoto genetic control rats (WKY). Left ventricular (LV) weight of SHRT was 17% lower (P less than .001) than that of SHR and 19% higher (P less than .01) than that of WKY. Collagen volume fraction of SHR (13.7 +/- 3.2%) and SHRT (9.9 +/- 1.8%) were greater (P less than .01) than WKY (5.0 +/- 1.9%). Diastolic and systolic stress-strain relations were determined in the isolated heart. A comparison of these relations revealed: 1) a 24% increase in passive stiffness for SHR and SHRT; and 2) a reduced zero-strain intercept (41% to 54%) and slope (36% to 48%) of the developed stress-strain relation for the SHRT. Thus, in SHR, collagen remodeling occurred in the absence of hypertrophy which suggests that the muscular and collagenous compartments of the myocardium are under separate controls. The excess accumulation of collagen in SHR and SHRT leads to abnormal passive stiffness, and the prevention of hypertrophy with hydralazine reduces active stiffness.

Animals↗
PubMed2001

Maximum entropy approach for modeling random uncertainties in transient elastodynamics.

A new approach is presented for analyzing random uncertainties in dynamical systems. This approach consists of modeling random uncertainties by a nonparametric model allowing transient responses of mechanical systems submitted to impulsive loads to be predicted in the context of linear structural dynamics. The information used does not require the description of the local parameters of the mechanical model. The probability model is deduced from the use of the entropy optimization principle, whose available information is constituted of the algebraic properties related to the generalized mass, damping, and stiffness matrices which have to be positive-definite symmetric matrices, and the knowledge of these matrices for the mean reduced matrix model. An explicit construction and representation of the probability model have been obtained and are very well suited to algebraic calculus and to Monte Carlo numerical simulation in order to compute the transient responses of structures submitted to impulsive loads. The fundamental properties related to the convergence of the stochastic solution with respect to the dimension of the random reduced matrix model are analyzed. Finally, an example is presented.

Journal Article↗
PubMed2006

Effect of storage upon material properties of lyophilized porcine extracellular matrix derived from the urinary bladder.

Xenogeneic extracellular matrices (ECMs) have been developed as off-the-shelf biologic scaffolds that have been effectively used in preclinical and clinical applications for tissue reconstruction. Such materials must be suitable for terminal sterilization and capable of storage for extended periods of time without significant changes in material properties and bioactivity. Material properties of interest for ECM scaffolds include hydrostatic permeability index (PI), uniaxial maximum load and elongation, maximum tangential stiffness (MTS), suture retention strength (SRS), and ball-burst strength (BBS). The present study evaluated these material properties for lyophilized forms of an ECM scaffold derived from the porcine urinary bladder, termed urinary bladder matrix (UBM), that was terminally sterilized by e-beam irradiation at 22 kGy and stored at room temperature (RT; 20-24 degrees C) or refrigerated temperature (REFT; 4-8 degrees C) for up to 12 months. UBM devices showed no change in SRS, BBS, and hydrostatic PI after the evaluation period. Lyophilized devices stored at RT showed an increase in maximum load and MTS while devices stored at REFT showed an increase in maximum elongation after 1 year of storage (p < 0.05). These results indicate that structural changes in the UBM device may slowly occur as a function of prolonged storage and storage temperature.

Animals↗
PubMedDate not supplied

In vivo fatigue microcracks in human bone: material properties of the surrounding bone matrix.

Human bones sustain fatigue damage in the form of in vivo microcracks as a result of the normal everyday loading activities. These microcracks appear to preferentially accumulate in certain regions of bone and most notably in interstitial bone matrix areas. These are remnants of old bone tissue left unremodelled, which show a higher than average mineral content and consequently the occurrence of microcracks has been attributed to the possible brittleness brought about by such hypermineralisation. There is a need, therefore, for information on the in situ bone matrix properties in the vicinity of such in vivo microcracks to elucidate the possible causes of their appearance. The present study examined the elastic, strain rate (viscous) and plastic properties of bone matrix in selectively targeted areas by nanoindentation and in both quasistatic and dynamic mode. The results showed that in vivo crack areas are not as stiff as some well-known extremely mineralised and brittle bone examples (bulla, rostrum); the strain rate effects of crack regions were identical to those of other regions of human bone and agreed well with values collected for human bone in the past at the macroscale; while the plasticity index of the crack regions was also not statistically different from most bone examples (including human at random, bovine, bulla and rostrum) except antler, which showed lower plasticity and thus a greater fraction of elastic recovery in indentation energy. It is difficult, therefore, to explain the susceptibility of these interstitial regions to crack in terms of the mineral content and its after-effects on elasticity, viscosity and plasticity alone, but one need to attribute the cracks to the cumulative loading history of these areas, or raise the suggestion that these areas of bone matrix are in some measure 'aged' or material/quality defective.

Aged↗
PubMed2026

Matrix Mechanics Governs Mechano-Metabolic Adaptation across Cancer Grades in Bladder Spheroids.

Extracellular matrix (ECM) mechanics is pivotal regulators of tumor progression, yet how viscoelasticity and matrix architecture converge to shape metabolic and invasive adaptation remains insufficiently defined. We postulate that mechanical stimuli from the ECM induce coordinated changes in adhesive and metabolic pathways, and that the nature of this independent mechano-metabolic pathway is conserved across benign, low-invasive, and high-invasive bladder cancer phenotypes. Therefore, we engineered collagen-hyaluronan hydrogels with tunable stiffness to recapitulate soft and rigid tumor microenvironments and profiled bladder cancer spheroids representing benign, low-invasive, and highly invasive states. Integrating hydraulic force spectroscopy, rheology, and molecular phenotyping, we show that matrix stiffening differentially reprograms spheroid architecture, motility, and adhesion- and metabolism-related gene expression. Spheroid behavior emerged from the interplay between intrinsic mechanical properties, matrix rheology, and molecular adaptation. HCV29 spheroids formed rigid, compact structures, relying on cell-matrix adhesion rather than metabolic or proteolytic remodeling. HT1376 spheroids activated glycolysis (HK2) and MMP-2-dependent ECM remodeling in soft matrices, but remained largely nonmigratory, indicating decoupling of invasive priming from motility. T24 spheroids were soft, deformable, and highly migratory in compliant matrices, integrating metabolic reprogramming, adhesion remodeling (E-/N-cadherin, SDC4), and radial collagen fiber alignment to drive invasion. Notably, canonical FAK/AKT/mTOR signaling was absent across all spheroids, while pS6 ribosomal protein and ILK indicated noncanonical, SDC4/integrin-ILK-dependent mechanotransduction supporting cytoskeletal dynamics, metabolism, and ECM remodeling. Collagen organization further differed across spheroid types, with dense, radially aligned fibers in HT1376, intermediate architecture in HCV29, and loose, disorganized networks in T24, closely matching their distinct migratory behaviors and cell-ECM interactions. These findings reveal stage-specific mechanometabolic strategies in bladder cancer, demonstrating how ECM mechanics and architecture jointly guide invasion, metabolic adaptation, and local immune modulation, including the regulation of immune cell infiltration and tumor immune evasion.

Humans↗
PubMed2005

A role for T lymphocytes in mediating cardiac diastolic function.

The induction of T helper (TH) lymphocytes by distinct TH ligands results in a differentiation to TH1/TH2 subsets based on their unique pattern of cytokine secretion and effector functions. We hypothesized that the relative proportion of TH1/TH2 directly relates to cardiac fibroblast (CF) function and thereby cardiac extracellular matrix (ECM) composition and cardiac diastolic function in the absence of injury or altered wall stress. We compared the effect of selective TH1 with TH2 inducers on cardiac gene expression, ECM composition, and diastolic function in C57BL/J mice. Twelve weeks after immune modulation, the left ventricular stiffness (beta) was significantly increased in the TH1 group and decreased in the TH2 group (P < 0.01). The TH2 group also demonstrated significantly increased end-diastolic and end-systolic volumes (P < 0.01). Cardiac gene expression patterns for pro-matrix metalloproteinase (MMP)-9 and -13 were increased by greater than fivefold in the TH2 group and significantly decreased in the TH1 group (P < 0.05). The total cardiac collagen and cross-linked collagen were significantly increased in the TH1 group and decreased in the TH2 group (P < 0.01). Coculturing lymphocytes harvested from the treated mice with naive primary CF demonstrated a direct control of the lymphocytes on CF pro-collagen, pro-MMP gene expression, and MMP activity. These results suggest that the TH phenotype differentially affects diastolic function through modulating CF pro-collagen and pro-MMP gene expression, MMP activity, and cardiac collagen cross-linking, resulting in altered ECM composition. Thus modulation of TH lymphocyte function could promote adaptive remodeling in heart failure and postmyocardial infarction.

Animals↗
PubMed1999

Osseointegration of sintered porous-surfaced and plasma spray-coated implants: An animal model study of early postimplantation healing response and mechanical stability.

The osseointegration and long-term success of bone-interfacing implants are dependent on mechanical stability of the implant relative to host bone during the early healing period. The geometric design of an implant surface may play an important role in affecting early implant stabilization, possibly by influencing tissue healing dynamics. In this study, we compared the early tissue healing response and resulting implant stability for two surface designs by characterizing the histological and mechanical properties of the healing tissue around Ti6Al4V sintered porous-surfaced and Ti plasma-sprayed implants. The implants were inserted transversely in rabbit femoral condyles and evaluated at 0, 4, 8, and 16 days postimplantation. At 4 and 8 days after implantation, the early healing tissue (fibrin and collagenous matrix) was more extensively integrated with the three-dimensional interconnected structure of the sintered porous surface than with the irregular geometry of the plasma-sprayed coating. In addition, histological examination indicated that initial matrix mineralization leading to osseointegration occurred more rapidly with the porous-surfaced implants. The more extensive tissue integration and more rapid matrix mineralization with the porous-surfaced implants were reflected in the mechanical test data, which demonstrated greater attachment strength and interfacial stiffness for the porous-surfaced implants 4 and 8 days postimplantation (p <.05). Sixteen days after implantation, both implant designs were osseointegrated and had comparable attachment characteristics. These data demonstrate that appropriate surface design selection can improve early implant stability and induce an accelerated healing response, thereby improving the potential for implant osseointegration.

Animals↗
PubMed2005

Nanomechanical properties of silica-coated multiwall carbon nanotubes-poly(methyl methacrylate) composites.

The mechanical properties of polymer composites, reinforced with silica-coated multiwall carbon nanotubes (MWNTs), have been studied using the nanoindentation technique. The hardness and the Young's modulus have been found to increase strongly with the increasing content of these nanotubes in the polymer matrix. Similar experiments conducted on thin films containing MWNTs, but without a silica shell, revealed that the presence of these nanotubes does not affect the nanomechanical properties of the composites. While carbon nanotubes (CNTs) have a very high tensile strength due to the nanotube stiffness, composites fabricated with CNTs may exhibit inferior toughness. The silica shell on the surface of a nanotube enhances its stiffness and rigidity. Our composites, at 4 wt % of the silica-coated MWNTs, display a maximum hardness of 120 +/- 20 MPa, and a Young's modulus of 9 +/- 1 GPa. These are respectively 2 and 3 times higher than those for the polymeric matrix. Here, we describe a method for the silica coating of MWNTs. This is a simple and efficient technique, adaptable to large-scale production, and might lead to new advanced polymer based materials, with very high axial and bending strength.

Journal Article↗