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PubMed2000

High strength bioresorbable bone plates: preparation, mechanical properties and in vitro analysis.

Biodegradable bone plates were prepared as semi-interpenetrating networks (SIPN) of crosslinked polypropylene fumarate (PPF) within a host matrix of either poly(lactide-co-glycolide)-85:15 (PLGA) or poly(1-lactide-co-d,l-lactide)-70:30 (PLA) using N-vinylpyrrolidone (NVP), ethylene glycol dimethacrylate (EGDMA), 2-hydroxyethyl methacrylate (HEMA), and methyl methacrylate (MMA) as crosslinking agents. Hydroxyapatite (HAP), an inorganic filler material, was used to further augment mechanical strength. The control crosslinking agent (NVP) was replaced partially and totally with other crosslinking agents. The amount of crosslinking agent lost, the characterization change in the mechanical properties and the dimensional stability of the bone plates after in vitro treatment was calculated. The optimum crosslinking agent was selected on the basis of low in vitro release of NVP from SIPN matrix. Bone plates were then prepared using this crosslinking agent at 5 MPa pressure and at temperatures between 100-140 degrees C to determine if there was any augmentation of mechanical properties in the presence of the crosslinked network. In vitro analysis showed that 90% of the crosslinking agent was lost on plates using NVP as a crosslinking agent. This loss was reduced to 50% when NVP was partially replaced with EGDMA or MMA. EGDMA was determined to be superior because (1) its low release as a crosslinking agent, (2) flexural plate strength of 50-67 MPa, (3) flexural modulus of 7-13 GPa, and (4) manufacturability stiffness of 300-600 N/m. HAP-loading resulted in an additional increase in values of mechanical parameters. Substituting PLGA with PLA in the PPF-SIPN did not show any additional improvement of mechanical properties.

Absorbable Implants↗
PubMed2004

Altered tissue properties induce changes in cancellous bone architecture in aging and diseases.

The mechanical properties of cancellous bone depend on its architecture and the tissue properties of the mineralized matrix. The architecture is continuously adapted to external loads. In this paper, it was assumed that changes in tissue properties leading to changes in tissue deformation can induce adaptation of the architecture. We asked whether changes in cancellous bone architecture with aging and in e.g. early osteoarthrosis can be explained from changes in tissue properties. This was investigated using computer models in which the cancellous architecture was adapted to external loads. Bone tissue with deformations below a certain threshold was resorbed, deformations above another threshold induced formation. Deformations between these two boundaries, in the 'lazy zone', did not induce bone adaptation. The effects of changes in bone tissue stiffness on bone mass, global stiffness and architecture were investigated. The bone gain (40-60%) resulting from a 50% decrease in tissue stiffness (simulating diseased tissue) was much larger than the bone loss (2-30%) resulting from a 50% increase in tissue stiffness (simulating highly mineralized, old tissue). The adaptation induced by a decrease in tissue stiffness resulted in an almost constant stiffness in the main load bearing direction, but the transversal stiffness decreased. An increased tissue stiffness resulted in a higher stiffness in the main direction and overcompensation in the transversal directions: the global stiffness could become even smaller than the stiffness of the original model. Concluding, we showed that changes in trabecular bone in aging and diseases can be partly explained from changes in tissue properties.

Adaptation, Physiological↗
PubMed1993

Nonlinear response analysis of the human ligamentous lumbar spine in compression. On mechanisms affecting the postural stability.

Basic questions regarding how extreme compressive loads can be tolerated by the spine without experiencing abnormal motions or instabilities remain unresolved. Two finite element models of the human lumbar spine were generated. The detailed model accounted for the three-dimensional irregular geometry, material and geometric nonlinearities, nonhomogeneous fiber-matrix nature of the discs, ligaments, and articulation at the facet joints. The nonlinear stability response of the model was predicted under an axial compression force (200 N to 700 N) applied at the L1 while the S1 was fixed. The effect of the presence of a combined flexion moment and a horizontal support on the response was investigated. Another nonlinear model using rigid bodies interconnected by deformable beam elements was also considered. The computed results under the axial compression loads indicated that the response is highly nonlinear with no bifurcation or limit point (critical load). The unconstrained lumbar spine is most flexible in the sagittal plane (least stiff plane). The existence of the horizontal support and the combined flexion moment significantly increased the load-bearing capacity of the lumbar spine; the lumbar spine resisted the axial compression force of 400 N with minimal displacements. Under axial compression force, the flexion moment tends to restrict the posterior translational movement of the lordotic lumbar spine, whereas the horizontal support constrains the coupled lateral motion. A slight decrease in the lordosis was predicted for the compression load of 400 N. It is postulated that the anterior location of the line of gravity of the upper-body weight is regulated to provide the required combined loads on the lumbar spine so higher compression can be tolerated by the spine at minimal energetic cost. In vivo experimental results support the validity of the model predictions.

Aged↗
PubMed2000

Prinomastat, a hydroxamate-based matrix metalloproteinase inhibitor. A novel pharmacological approach for tissue remodelling-related diseases.

Prinomastat (formerly AG3340, Agouron Pharmaceuticals, Inc.) is a potent, selective oral inhibitor of matrix metalloproteinase-2, -9, -13 and -14. This peculiar selectivity should represent an advantage for prinomastat in terms of efficacy/tolerability. The drug has been shown to inhibit tumour growth and angiogenesis in a variety of preclinical models, including cancer of colon, breast, lung and intriguingly in melanoma and glioma models. Moreover, the combination of prinomastat and several chemotherapeutic agents was shown to induce additive effects. The drug is currently in Phase III clinical trials for patients with non-small cell lung cancer in combination with paclitaxel and carboplatin, as well as in advanced hormone refractory prostate cancer in combination with mitoxantrone. The most common side effects are musculoskeletal pain and stiffness. These side effects generally cease with treatment interruption. Finally, considering the pathophysiology of MMPs, Agouron is exploring the utility of prinomastat in ophthalmology and dermatology.

Animals↗
PubMed2004

Role of extracellular matrix in adaptation of tendon and skeletal muscle to mechanical loading.

The extracellular matrix (ECM), and especially the connective tissue with its collagen, links tissues of the body together and plays an important role in the force transmission and tissue structure maintenance especially in tendons, ligaments, bone, and muscle. The ECM turnover is influenced by physical activity, and both collagen synthesis and degrading metalloprotease enzymes increase with mechanical loading. Both transcription and posttranslational modifications, as well as local and systemic release of growth factors, are enhanced following exercise. For tendons, metabolic activity, circulatory responses, and collagen turnover are demonstrated to be more pronounced in humans than hitherto thought. Conversely, inactivity markedly decreases collagen turnover in both tendon and muscle. Chronic loading in the form of physical training leads both to increased collagen turnover as well as, dependent on the type of collagen in question, some degree of net collagen synthesis. These changes will modify the mechanical properties and the viscoelastic characteristics of the tissue, decrease its stress, and likely make it more load resistant. Cross-linking in connective tissue involves an intimate, enzymatical interplay between collagen synthesis and ECM proteoglycan components during growth and maturation and influences the collagen-derived functional properties of the tissue. With aging, glycation contributes to additional cross-linking which modifies tissue stiffness. Physiological signaling pathways from mechanical loading to changes in ECM most likely involve feedback signaling that results in rapid alterations in the mechanical properties of the ECM. In developing skeletal muscle, an important interplay between muscle cells and the ECM is present, and some evidence from adult human muscle suggests common signaling pathways to stimulate contractile and ECM components. Unaccostumed overloading responses suggest an important role of ECM in the adaptation of myofibrillar structures in adult muscle. Development of overuse injury in tendons involve morphological and biochemical changes including altered collagen typing and fibril size, hypervascularization zones, accumulation of nociceptive substances, and impaired collagen degradation activity. Counteracting these phenomena requires adjusted loading rather than absence of loading in the form of immobilization. Full understanding of these physiological processes will provide the physiological basis for understanding of tissue overloading and injury seen in both tendons and muscle with repetitive work and leisure time physical activity.

Animals↗
PubMed2000

Towards a fibrous composite with dynamically controlled stiffness: lessons from echinoderms.

Sea urchins and sea cucumbers, like other echinoderms, control the tensile properties of their connective tissues by regulating stress transfer between collagen fibrils. The collagen fibrils are spindle-shaped and up to 1 mm long with a constant aspect ratio of approx. 2000. They are organized into a tissue by an elastomeric network of fibrillin microfibrils. Interactions between the fibrils are regulated by soluble macromolecules that are secreted by local, neurally controlled, effector cells. We are characterizing the non-linear viscoelastic properties of sea cucumber dermis under different conditions, as well as the structures, molecules and molecular interactions that determine its properties. In addition, we are developing reagents that will bind covalently to fibril surfaces and reversibly form cross-links with other reagents, resulting in a chemically controlled stress-transfer capacity. The information being developed will lead to the design and construction of a synthetic analogue composed of fibres in an elastomeric matrix that contains photo- or electro-sensitive reagents that reversibly form interfibrillar cross-links.

Animals↗
PubMed2003

An ionised/non-ionised dual porosity model of intervertebral disc tissue.

The volume of the intrafibrillar water space--i.e. the water contained inside the collagen fibres--is a key parameter that is relevant to concepts of connective tissue structure and function. Confined compression and swelling experiments on annulus fibrosus samples are interpreted in terms of a dual porosity model that distinguishes between a non-ionised intrafibrillar porosity and an ionised extrafibrillar porosity. Both porosities intercommunicate and are saturated with a monovalent ionic solution, i.c. NaCl. The extrafibrillar fixed charge density of the samples is assessed using radiotracer techniques and the collagen content is evaluated by measurement of hydroxyproline concentration. The interpretation of the experimental data yields values for the intrafibrillar water content, the average activity coefficient of the ions, the Donnan osmotic coefficient, the fraction of intrafibrillar water, the stress-free deformation state, and an effective stress-strain relationship as a function of the radial position in the disc. A linear fit between the second Piola-Kirchhoff effective stress and Green-Lagrange strain yielded an effective stiffness: H(e)=1.087 +/- 0.657 MPa. The average fraction of intrafibrillar water was 1.16 g/g collagen. The results were sensitive to changes in the activity and osmotic coefficients and the fraction of intrafibrillar water. The fixed charge density increased with distance from the outer edge of the annulus, whereas the hydroxyproline decreased.

Animals↗
PubMed2006

Neutrophils modulate post-thrombotic vein wall remodeling but not thrombus neovascularization.

Early deep venous thrombosis (DVT) resolution is associated with neutrophil (PMN) influx. This study examined the role of PMNs in thrombus neovascularization and vein wall injury after DVT. A rat model of DVT by inferior vena cava (IVC) ligation was performed with control serum or rabbit anti-rat PMN serum administered perioperatively with sacrifice at 2 and 7 days. At 2 days, neutropenic rats had 1.6-fold larger thrombi (P = .04) and 1.4-fold higher femoral venous pressures by water manometry (P = .008) but no difference in thrombus neovascularization was observed. By 7 days, DVT sizes were similar, but vein wall injury persisted in the neutropenic rats with a 2.0-fold increase in vein wall stiffness by microtensiometry (P < .05), as well as a 1.2-fold increased thickness (P = .04). Collagen and profibrotic growth factors were significantly increased in neutropenic IVC at 7 days (all P < .05). Vein wall and intrathrombus uPA byWestern immunoblotting, and intrathrombus MMP-9 gelatinase activity were significantly less in neutropenic rats than controls (P < .001). Conversely, MMP-2 was significantly elevated in neutropenic IVC at 2 days after DVT. However, neutropenia induced 24 hours after DVT formation resulted in no significant increase in vein wall stiffness or collagen levels at 7 days, despite 1.4-fold larger thrombi (P < .05). These data suggest a critical early role for PMN in post DVT vein wall remodeling.

Animals↗
PubMed1993

Viscoelasticity of the sarcomere matrix of skeletal muscles. The titin-myosin composite filament is a dual-stage molecular spring.

The mechanical roles of sarcomere-associated cytoskeletal lattices were investigated by studying the resting tension-sarcomere length curves of mechanically skinned rabbit psoas muscle fibers over a wide range of sarcomere strain. Correlative immunoelectron microscopy of the elastic titin filaments of the endosarcomeric lattice revealed biphasic extensibility behaviors and provided a structural interpretation of the multiphasic tension-length curves. We propose that the reversible change of contour length of the extensible segment of titin between the Z line and the end of thick filaments underlies the exponential rise of resting tension. At and beyond an elastic limit near 3.8 microns, a portion of the anchored titin segment that adheres to thick filaments is released from the distal ends of thick filament. This increase in extensible length of titin results in a net length increase in the unstrained extensible segment, thereby lowering the stiffness of the fiber, lengthening the slack sarcomere length, and shifting the yield point in postyield sarcomeres. Thus, the titin-myosin composite filament behaves as a dual-stage molecular spring, consisting of an elastic connector segment for normal response and a longer latent segment that is recruited at and beyond the elastic limit of the sarcomere. Exosarcomeric intermediate filaments contribute to resting tension only above 4.5 microns. We conclude that the interlinked endo- and exosarcomeric lattices are both viscoelastic force-bearing elements. These distinct cytoskeletal lattices appear to operate over two ranges of sarcomere strains and collectively enable myofibrils to respond viscoelastically over a broad range of sarcomere and fiber lengths.

Animals↗
PubMed2004

Serum cartilage oligomeric matrix protein (COMP) in rheumatoid arthritis and knee osteoarthritis.

The cartilage oligometrix matrix protein (COMP) is a noncollagenous protein, a glycoprotein, the function of which is to bind to type II collagen fibres and stabilise the collagen fibre network in the articular cartilage. In the serum of the normal population the COMP level is 5 mug/ml. An increased level of COMP in the synovial fluid was described in the early stage of rheumatoid arthritis (RA), whereas in advanced stages of RA, the level of COMP decreased. In this study we assessed the serum COMP level in patients with RA and knee osteoarthritis (OA) and found a correlation between the serum COMP level and other markers as well as bone mass density (BMD) changes, activity of disease, disease duration and the age of the patients. The blood was collected from 30 RA patients and 30 OA patients who constituted the control group. The serum COMP level was determined using an inhibition enzyme-linked immunosorbent assay (ELISA). The average value of the serum COMP level in RA patients was 10.4+/-3.6 U/l. There was a correlation between the serum COMP level and the age of RA patients (p<0.005) and disease activity score (DAS) value (p<0.01). According to correlation coefficients, the serum COMP level was independent of stage of disease, number of painful and swollen joints, duration of morning stiffness, disease duration and titre of the Waaler-Rose test. The influence of rheumatoid nodule presence on the serum COMP level was shown (p<0.05). In RA patients with erythrocyte sedimentation rate (ESR) values below 20 mm/h compared with patients with ESR values over 60 mm/h, the serum COMP level was observed to be significantly lower (p<0.05). The average value of COMP in OA patients was 10.4+/-2.7 U/l. No correlation was found between the serum COMP level and patients' age and disease duration. There was a correlation between the serum COMP level and Western Ontario and McMaster Universities (WOMAC) index pain scale for the lower limbs (p<0.005) and T-score value of densitometry examinations (p<0.036) in OA patients. No statistical differences were found between the average serum COMP level in RA and OA patients.

Absorptiometry, Photon↗
PubMed1997

Expression of a truncated, kinase-defective TGF-beta type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis.

Members of the TGF-beta superfamily are important regulators of skeletal development. TGF-betas signal through heteromeric type I and type II receptor serine/threonine kinases. When over-expressed, a cytoplasmically truncated type II receptor can compete with the endogenous receptors for complex formation, thereby acting as a dominant-negative mutant (DNIIR). To determine the role of TGF-betas in the development and maintenance of the skeleton, we have generated transgenic mice (MT-DNIIR-4 and -27) that express the DNIIR in skeletal tissue. DNIIR mRNA expression was localized to the periosteum/perichondrium, syno-vium, and articular cartilage. Lower levels of DNIIR mRNA were detected in growth plate cartilage. Transgenic mice frequently showed bifurcation of the xiphoid process and sternum. They also developed progressive skeletal degeneration, resulting by 4 to 8 mo of age in kyphoscoliosis and stiff and torqued joints. The histology of affected joints strongly resembled human osteo-arthritis. The articular surface was replaced by bone or hypertrophic cartilage as judged by the expression of type X collagen, a marker of hypertrophic cartilage normally absent from articular cartilage. The synovium was hyperplastic, and cartilaginous metaplasia was observed in the joint space. We then tested the hypothesis that TGF-beta is required for normal differentiation of cartilage in vivo. By 4 and 8 wk of age, the level of type X collagen was increased in growth plate cartilage of transgenic mice relative to wild-type controls. Less proteoglycan staining was detected in the growth plate and articular cartilage matrix of transgenic mice. Mice that express DNIIR in skeletal tissue also demonstrated increased Indian hedgehog (IHH) expression. IHH is a secreted protein that is expressed in chondrocytes that are committed to becoming hypertrophic. It is thought to be involved in a feedback loop that signals through the periosteum/ perichondrium to inhibit cartilage differentiation. The data suggest that TGF-beta may be critical for multifaceted maintenance of synovial joints. Loss of responsiveness to TGF-beta promotes chondrocyte terminal differentiation and results in development of degenerative joint disease resembling osteoarthritis in humans.

Animals↗
PubMed2001

Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats.

Fibrosis leads to chronic impairment of cardiac and renal function and thus reversal of existing fibrosis may improve function and survival. This project has determined whether pirfenidone, a new antifibrotic compound, and spironolactone, an aldosterone antagonist, reverse both deposition of the major extracellular matrix proteins, collagen and fibronectin, and functional changes in the streptozotocin(STZ)-diabetic rat. Streptozotocin (65 mg kg(-1) i.v.)-treated rats given pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone; approximately 200 mg kg(-1) day(-1) as 0.2 - 2g 1(-1) drinking water) or spironolactone (50 mg kg(-1) day(-1) s.c.) for 4 weeks starting 4 weeks after STZ showed no attenuation of the increased blood glucose concentrations and increased food and water intakes which characterize diabetes in this model. STZ-treatment increased perivascular and interstitial collagen deposition in the left ventricle and kidney, and surrounding the aorta. Cardiac, renal and plasma fibronectin concentrations increased in STZ-diabetic rats. Passive diastolic stiffness increased in isolated hearts from STZ-diabetic rats. Both pirfenidone and spironolactone treatment attenuated these increases without normalizing the decreased +dP/dt(max) of STZ-diabetic hearts. Left ventricular papillary muscles from STZ-treated rats showed decreased maximal positive inotropic responses to noradrenaline, EMD 57033 (calcium sensitizer) and calcium chloride; this was not reversed by pirfenidone or spironolactone treatment. STZ-treatment transiently decreased GFR and urine flow rates in isolated perfused kidneys; pirfenidone but not spironolactone prevented the return to control values. Thus, short-term pirfenidone and spironolactone treatment reversed cardiac and renal fibrosis and attenuated the increased diastolic stiffness without normalizing cardiac contractility or renal function in STZ-diabetic rats.

Animals↗
PubMed2005

From stem cells to viable autologous semilunar heart valve.

BACKGROUND: An estimated 275,000 patients undergo heart valve replacement each year. However, existing solutions for valve replacement are complicated by the morbidity associated with lifelong anticoagulation of mechanical valves and the limited durability of bioprostheses. Recent advances in tissue engineering and our understanding of stem cell biology may provide a lifelong solution to these problems. METHODS AND RESULTS: Mesenchymal stem cells were isolated from ovine bone marrow and characterized by their morphology and antigen expression through immunocytochemistry, flow cytometry, and capacity to differentiate into multiple cell lineages. A biodegradable scaffold was developed and characterized by its tensile strength and stiffness as a function of time in cell-conditioned medium. Autologous semilunar heart valves were then created in vitro using mesenchymal stem cells and the biodegradable scaffold and were implanted into the pulmonary position of sheep on cardiopulmonary bypass. The valves were evaluated by echocardiography at implantation and after 4 months in vivo. Valves were explanted at 4 and 8 months and examined by histology and immunohistochemistry. Valves displayed a maximum instantaneous gradient of 17.2+/-1.33 mm Hg, a mean gradient of 9.7+/-1.3 mm Hg, an effective orifice area of 1.35+/-0.17 cm2, and trivial or mild regurgitation at implantation. Gradients changed little over 4 months of follow-up. Histology showed disposition of extracellular matrix and distribution of cell phenotypes in the engineered valves reminiscent of that in native pulmonary valves. CONCLUSIONS: Stem-cell tissue-engineered heart valves can be created from mesenchymal stem cells in combination with a biodegradable scaffold and function satisfactorily in vivo for periods of >4 months. Furthermore, such valves undergo extensive remodeling in vivo to resemble native heart valves.

Animals↗
PubMed1995

[Visco-elasticity of transplanted menisci in rabbits. A correlative histological and hydrodynamical studies].

The purpose of this study is to investigate the visco-elasticity, histology and hydrodynamics of transplanted menisci following transplantation. Experiments to examine visco-elasticity are performed on 30 rabbits, to examine NMR on 20 rabbits and on 12 rabbits respectively for histological study. Under intravenous general anesthesia the medial meniscus was completely resected, and a cryopreserved allograft meniscus was implanted. The rabbits are sacrificed 1, 2, 3 and 5 months post-operatively, and the implanted menisci are removed for examination. One month after surgery, dynamic stiffness is markedly lower in the implanted menisci than in the controls. Thereafter, it gradually increased. Three months after surgery, there is no significant difference between the transplanted menisci and the controls. However the value of tan delta which serves as indicator of dynamic visco-elasticity is larger in the implanted menisci than in the control specimens throughout the experiment. The water content was higher in the transplanted menisci throughout. The 1H-NMR relaxation time (T2) was markedly prolonged 1 month post-operatively, but shortened rapidly after that. Nevertheless, it is still longer than in the control specimen after 5 months. In the histological study, no chondrocytes are observed in the transplanted menisci, and the matrix was poorly stained with Eosin 1 month after surgery. Thereafter, granulomatous tissues proliferated in the menisci, and by 5 months after surgery, the chondrocytes appear to be almost normal. However, matrix was weakly stained with Eosin. These results suggest that the interactions between high molecular weight matrix and water in transplanted menisci are different from those in normal menisci, and that therefore the viscosity of transplanted menisci is higher.

Animals↗
PubMed2001

The effect of NKISK on tendon in an in vivo model.

The mechanism through which ligaments and tendons change length during growth and contracture is unclear. It has been hypothesized that there is a reversible "interfibrillar bond" that, when broken, allows the sliding of collagen fibrils past one another during length changes. The pentapeptide NKISK has been reported to inhibit the binding of decorin to fibronectin. This study was designed to evaluate the effect of NKISK in an in vivo model. Male Sprague-Dawley rats were divided into three groups (n = 9, 9 and 14, respectively). The left patellar tendon was injected with 1.0 ml of NKISK (Group 1 = 1.0 mM, Groups 2 and 3 = 5.0 mM). The contralateral/control limb was injected with carrier. Group 1 was sacrificed after three, Group 2 after four and Group 3 after seven daily injections. The patellar tendon lengths were measured in all groups with comparisons made to the contralateral control limb. NKISK injection resulted in a significant increase in length in Group 2 (3.14% +/- 2.04, P = 0.002) and in Group 3 (6.12% +/- 3.84, P < 0.001). Biomechanical testing of Group 3 showed no differences in maximum load, ultimate strength, structural stiffness, or elastic modulus of the treated tendons but did demonstrate a statistically significant decrease in the displacement and strain at maximum load in the NKISK-treated tendons. This study demonstrates that inhibition of decorin/fibronectin binding by NKISK results in tendon lengthening in an in vivo setting as noted by a progressive increase in the length of the patellar tendon.

Animals↗
PubMed2006

Exercise training blunts microvascular rarefaction in the metabolic syndrome.

Reduced skeletal muscle microvessel density (MVD) in the obese Zucker rat (OZR) model of the metabolic syndrome is a function of a chronic reduction in vascular nitric oxide (NO) bioavailability. Previous studies suggest that exercise can improve NO bioavailability and reduce chronic inflammation and that low vascular NO bioavailability may be associated with impaired angiogenic responses via increased matrix metalloproteinase (MMP)-2 and MMP-9 activity. As such, we hypothesized that chronic exercise (EX) would increase NO bioavailability in OZR and blunt microvascular rarefaction through reduced MMP activity, and potentially via altered plasma cytokine levels. Ten weeks of treadmill exercise (1 h/day, 5 days/wk, 22 m/min) reduced body mass and fasting insulin and triglyceride levels in EX-OZR vs. sedentary (SED) OZR. In EX-OZR, gastrocnemius muscle MVD was improved by 19 +/- 4%, whereas skeletal muscle arteriolar dilation and conduit arterial methacholine-induced NO release were increased. In EX-OZR, functional hyperemia was improved vs. SED-OZR, and minimum vascular resistance within perfused gastrocnemius muscle was reduced, although no change in arteriolar stiffness was identified. Western blotting and gelatin zymography demonstrated that neither expression nor activity of MMP-2 or MMP-9 was altered in skeletal muscle of EX vs. SED animals. Plasma markers of inflammation associated with angiogenesis, monocyte chemoattractant protein-1 and IL-1beta, were increased in SED-OZR and were reduced with training, whereas IL-13 was reduced in SED-OZR and increased with exercise. These data suggest that exercise-induced improvements in skeletal muscle MVD in OZR are associated with increased NO bioavailability and may stem from altered inflammatory profiles rather than MMP function.

Animals↗
PubMed2005

Changes in mechanical properties and cellularity during long-term culture of collagen fiber ACL reconstruction scaffolds.

Resorbable scaffolds for anterior cruciate ligament (ACL) reconstruction should provide temporary mechanical function then gradually breakdown while promoting matrix synthesis by local cells. Crosslinking influences collagen's mechanical properties, degradation rate, and interactions with cells. Our objective was to compare the effects of different crosslinkers on cellularity and mechanical properties during long-term (8 week) culture of collagen fiber scaffolds. Fibers were fabricated from an acid-insoluble dispersion of bovine dermal collagen and crosslinked with either ultraviolet irradiation (UV; a physical crosslinker) or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC; a chemical crosslinker). Scaffolds consisted of 50 fibers bundled in parallel. Initial attachment of fibroblasts was similar on both scaffolds; however, from 1 to 8 weeks in culture, UV-crosslinked scaffolds had significantly more cells attached than EDC-crosslinked scaffolds. The initial breaking load (3.50 N) and stiffness (2.23 N/mm) of EDC-crosslinked scaffolds were significantly greater than those of UV-crosslinked scaffolds (2.32 N; 1.21 N/mm) and were unaffected by long-term fibroblast culture. In contrast, the load-bearing capacity of fibroblast-seeded UV-crosslinked scaffolds decreased 60% to 0.91 N after 8 weeks in culture. EDC-crosslinked scaffolds maintained strength and moderate cellularity; UV-crosslinked scaffolds, in contrast, were highly cellular, but had poor mechanical properties that decreased during culture. These in vitro results suggest that collagen fiber scaffolds crosslinked with EDC may be more suitable for ACL reconstruction than those crosslinked with UV.

Absorbable Implants↗
PubMed2004

Phorbol ester-mediated pulmonary artery endothelial barrier dysfunction through regulation of actin cytoskeletal mechanics.

The mechanisms of phorbol ester- and thrombin-mediated pulmonary artery endothelial barrier dysfunction were compared. Phorbol ester dibutyrate (PDBU) mediated slow force velocity and less force than thrombin. Taxol did not attenuate PDBU-mediated tension, while it reversed nocodazole-mediated tension. PDBU-mediated tension was not affected by acrylamide; PDBU increased cell stiffness and produced greater declines in transendothelial resistance (TER) than acrylamide. Thus PDBU caused a net increase in tension and did not unload microtubule or intermediate filaments. Microfilament remodeling, determined on the basis of immunocytochemistry and actin solubility, lacked the sensitivity and specificity to predict actin-dependent mechanical properties. Thrombin increased myosin light chain (MLC) kinase site-specific MLC phosphorylation, according to peptide map analysis, whereas PDBU did not increase PKC-specific MLC phosphorylation. The initial PDBU-mediated tension development temporally correlated with PDBU-mediated decline in TER and increased low-molecular-weight caldesmon (l-CaD) phosphorylation. PDBU-mediated tension development and decreases in TER were associated with a temporal loss of endothelial cell-matrix adhesion, based on a numerical model of TER. Although, on the basis of immunocytochemistry, thrombin-mediated tension was associated with actin insolubility, actin reorganization, and gap formation, these changes did not predict thrombin-mediated gap formation, based on TER and time-lapse differential interference contrast microscopy. These data suggest that PDBU may disrupt endothelial barrier function through loss of cell-matrix adhesion through l-CaD-dependent actin contraction.

Actins↗