Awakening from sleep to urinate is the hallmark of nocturia, a condition that impacts several facets of health related quality of life and for which current therapy is suboptimal. Given the paucity of prospective data on antimuscarinics for the management of nocturia, we investigated the efficacy and safety of flexible dose fesoterodine for the treatment of nocturnal urgency in subjects with nocturia and overactive bladder.
Materials and Methods
Subjects with 2 to 8 nocturnal urgency episodes per 24 hours began a 2-week, single-blind, placebo run-in followed by 1:1 randomization to 12 weeks of double-blind treatment with fesoterodine (4 mg daily for 4 weeks with an optional increase to 8 mg) or placebo using predefined criteria for nocturnal urgency episodes, nocturnal urine volume voided and total 24-hour urine volume voided. The primary end point was change from baseline to week 12 in the mean number of micturition related nocturnal urgency episodes per 24 hours.
Overall 963 subjects were randomized from 2,990 screened, and 82% of subjects treated with fesoterodine and 84% of those treated with placebo completed the study. Significant improvements in the primary end point (−1.28 vs −1.07), in nocturnal micturitions per 24 hours (−1.02 vs −0.85) and in nocturnal frequency urgency sum (−4.01 vs −3.42) were observed with fesoterodine vs placebo (all p ≤0.01). Health related quality of life measures (overactive bladder questionnaire Symptom Bother −20.1 vs −16.5, sleep 22.3 vs 19.9 and other domains; all p <0.05) were improved with fesoterodine.
To our knowledge this is the first prospective study to assess antimuscarinic efficacy for reducing nocturnal urgency. Flexible dose fesoterodine significantly reduced nocturnal urgency episodes vs placebo in subjects with overactive bladder.
muscarinic antagonists; urinary bladder; overactive; nocturia; lower urinary tract symptoms; treatment outcome
The objective of this research was to examine the efficacy of evaluating the region of the glenohumeral capsule being tested by clinical exams for shoulder instability using finite element models of the glenohumeral joint. Specifically, the regions of high capsule strain produced by glenohumeral joint positions commonly used during a clinical exam were identified. Kinematics that simulated a simple translation test with an anterior load at three external rotation angles were applied to a validated, subject-specific finite element model of the glenohumeral joint at 60° of abduction. Maximum principal strains on the glenoid side of the IGHL were significantly higher than the maximum principal strains on the humeral side, for all three regions of the IGHL at 30° and 60° of external rotation. These regions of localized strain indicate that these joint positions might be used to test the glenoid side of the IGHL during this clinical exam, but are not useful for assessing the humeral side of the IGHL. The use of finite element models will facilitate the search for additional joint positions that isolate high strains to other IGHL regions, including the humeral side of the IGHL.
inferior glenohumeral ligament; soft tissue mechanics; strain; finite element
To utilize the surveillance, epidemiology, and end results database to analyze whether there are racial or socioeconomic disparities associated with the selection of prostate brachytherapy.
Material and methods
We selected patients who were diagnosed with localized prostate cancer between 2004-2006 and who underwent treatment with radiation. Data regarding race and estimates of socioeconomic status were also obtained by analyzing the average reported cost of living adjusted income in the SEER county from which the patient was treated, and dividing these results into quartiles. Multivariate logistic regression analysis was used to determine whether there were any disparities associated with brachytherapy use.
A total of 38 704 patients were included in the analysis. Most patients (57%) received EBRT alone, while the remaining 43% of patients had brachytherapy as a component of their treatment, either alone (30.2%) or in combination with EBRT (12.2%). On multivariate logistic regression, prostate brachytherapy use was less likely in African American patients with an odds ratio of 0.89 (95% CI: 0.84-0.95, p < 0.001), and was more likely to be used in those with higher socioeconomic status. Regarding socioeconomic status, the odds ratio for receiving brachytherapy was 1.65 (95% CI: 1.55-1.75) for the 25-50% quartile, 1.92 (95% CI: 1.81-2.04) for the 50-75% quartile, and 2.05 (95% CI: 1.93-2.18) for the 75-100% quartile, respectively (p < 0.001).
There do appear to be socioeconomic and racial disparities in the selection of prostate brachytherapy. These findings may have both significant equality of care as well as cost of care implications.
brachytherapy; prostate cancer; racial disparities; radiation; socioeconomic disparities
Human immunodeficiency virus (HIV-1) depends upon host-encoded proteins to facilitate its replication while at the same time inhibiting critical components of innate and/or intrinsic immune response pathways. To characterize the host cell response on protein levels in CD4+ lymphoblastoid SUP-T1 cells after infection with HIV-1 strain LAI, we used mass spectrometry (MS)-based global quantitation with iTRAQ (isobaric tag for relative and absolute quantification). We found 266, 60 and 22 proteins differentially expressed (DE) (P-value ≤ 0.05) at 4, 8, and 20 hours post-infection (hpi), respectively, compared to time-matched mock-infected samples. The majority of changes in protein abundance occurred at an early stage of infection well before the de novo production of viral proteins. Functional analyses of these DE proteins showed enrichment in several biological pathways including protein synthesis, cell proliferation, and T-cell activation. Importantly, these early changes before the time of robust viral production have not been described before.
Protein quantification; iTRAQ; HIV-1; T-cells; LC-MS/MS; Ribosomal proteins
Our objectives were to determine cartilage contact stress during walking, stair climbing and descending stairs in a well-defined group of normal volunteers and to assess variations in contact stress and area among subjects and across loading scenarios. Ten volunteers without history of hip pain or disease with normal lateral center-edge angle and acetabular index were selected. Computed tomography imaging with contrast was performed on one hip. Bone and cartilage surfaces were segmented from volumetric image data, and subject-specific finite element models were constructed and analyzed using a validated protocol. Acetabular contact stress and area were determined for seven activities. Peak stress ranged from 7.52±2.11 MPa for heel-strike during walking (233% BW) to 8.66±3.01 MPa for heel-strike during descending stairs (261% BW). Average contact area across all activities was 34% of the surface area of the acetabular cartilage. The distribution of contact stress was highly non-uniform, and more variability occurred among subjects for a given activity than among activities for a single subject. The magnitude and area of contact stress were consistent between activities, although inter-activity shifts in contact pattern were found as the direction of loading changed. Relatively small incongruencies between the femoral and acetabular cartilage had a large effect on the contact stresses. These effects tended to persist across all simulated activities. These results demonstrate the diversity and trends in cartilage contact stress in healthy hips during activities of daily living and provide a basis for future comparisons between normal and pathologic hips.
Hip; Finite Element; Biomechanics; Cartilage Contact Stresses; Cartilage Pressure
Many lesbian and bisexual (LB) women veterans may have been targets of victimization in the military based on their gender and presumed sexual orientation, and yet little is known regarding the health or mental health of LB veterans, nor the degree to which they feel comfortable receiving care in the VA.
The purpose of this study was to examine the prevalence of mental health and gender-specific conditions, VA healthcare satisfaction and trauma exposure among LB veterans receiving VA care compared with heterosexually-identified women veterans receiving.
Prospective cohort study of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) women veterans at two large VA facilities.
Three hundred and sixty five women veterans that completed a baseline survey. Thirty-five veterans (9.6 %) identified as gay or lesbian (4.7 %), or bisexual (4.9 %).
Measures included sexual orientation, military sexual trauma, mental and gender-specific health diagnoses, and VA healthcare utilization and satisfaction.
LB OEF/OIF veterans were significantly more likely to have experienced both military and childhood sexual trauma than heterosexual women (MST: 31 % vs. 13 %, p < .001; childhood sexual trauma: 60 % vs. 36 %, p = .01), to be hazardous drinkers (32 % vs. 16 %, p = .03) and rate their current mental health as worse than before deployment (35 % vs. 16 %, p < .001).
Many LB veterans have experienced sexual victimization, both within the military and as children, and struggle with substance abuse and poor mental health. Health care providers working with female Veterans should be aware of high rates of military sexual trauma and childhood abuse and refer women to appropriate VA treatment and support groups for sequelae of these experiences. Future research should focus on expanding this study to include a larger and more diverse sample of lesbian, gay, bisexual, and transgender veterans receiving care at VA facilities across the country.
lesbian; health services research; Veterans; women
Genome-wide mutagenesis was performed in mice to identify candidate genes for male infertility, for which the predominant causes remain idiopathic. Mice were mutagenized using N-ethyl-N-nitrosourea (ENU), bred, and screened for phenotypes associated with the male urogenital system. Fifteen heritable lines were isolated and chromosomal loci were assigned using low density genome-wide SNP arrays. Ten of the fifteen lines were pursued further using higher resolution SNP analysis to narrow the candidate gene regions. Exon sequencing of candidate genes identified mutations in mice with cystic kidneys (Bicc1), cryptorchidism (Rxfp2), restricted germ cell deficiency (Plk4), and severe germ cell deficiency (Prdm9). In two other lines with severe hypogonadism candidate sequencing failed to identify mutations, suggesting defects in genes with previously undocumented roles in gonadal function. These genomic intervals were sequenced in their entirety and a candidate mutation was identified in SnrpE in one of the two lines. The line harboring the SnrpE variant retains substantial spermatogenesis despite small testis size, an unusual phenotype. In addition to the reproductive defects, heritable phenotypes were observed in mice with ataxia (Myo5a), tremors (Pmp22), growth retardation (unknown gene), and hydrocephalus (unknown gene). These results demonstrate that the ENU screen is an effective tool for identifying potential causes of male infertility.
A finite element formulation of neutral solute transport across a contact interface between deformable porous media is implemented and validated against analytical solutions. By reducing the integral statements of external virtual work on the two contacting surfaces into a single contact integral, the algorithm automatically enforces continuity of solute molar flux across the contact interface, whereas continuity of the effective solute concentration (a measure of the solute mechano-chemical potential) is achieved using a penalty method. This novel formulation facilitates the analysis of problems in biomechanics where the transport of metabolites across contact interfaces of deformable tissues may be of interest. This contact algorithm is the first to address solute transport across deformable interfaces, and is made available in the public domain, open-source finite element code FEBio (http://mrl.sci.utah.edu/software).
Finite element modeling; contact mechanics; solute transport; porous media; biphasic theory
RNA-based next-generation sequencing (RNA-Seq) provides a tremendous amount of new information regarding gene and transcript structure, expression and regulation. This is particularly true for non-coding RNAs where whole transcriptome analyses have revealed that the much of the genome is transcribed and that many non-coding transcripts have widespread functionality. However, uniform resources for raw, cleaned and processed RNA-Seq data are sparse for most organisms and this is especially true for non-human primates (NHPs). Here, we describe a large-scale RNA-Seq data and analysis infrastructure, the NHP reference transcriptome resource (http://nhprtr.org); it presently hosts data from12 species of primates, to be expanded to 15 species/subspecies spanning great apes, old world monkeys, new world monkeys and prosimians. Data are collected for each species using pools of RNA from comparable tissues. We provide data access in advance of its deposition at NCBI, as well as browsable tracks of alignments against the human genome using the UCSC genome browser. This resource will continue to host additional RNA-Seq data, alignments and assemblies as they are generated over the coming years and provide a key resource for the annotation of NHP genomes as well as informing primate studies on evolution, reproduction, infection, immunity and pharmacology.
Instability is a significant concern in total hip arthroplasty, particularly when there is structural compromise of the capsule due to pre-existing pathology or due to necessities of surgical approach. An experimentally grounded fiber-direction-based finite element model of the hip capsule was developed, and was integrated with an established three-dimensional model of impingement/dislocation. Model validity was established by close similarity to results from a cadaveric experiment in a servohydraulic hip simulator. Parametric computational runs explored effects of graded levels of capsule thickness, of regional detachment from the capsule’s femoral or acetabular insertions, of surgical incisions of capsule substance, and of capsule defect repairs. Depending strongly upon the specific site, localized capsule defects caused varying degrees of construct stability compromise, with several specific situations involving over 60% decrement in dislocation resistance. Construct stability was returned substantially toward intact-capsule levels following well conceived repairs, although the suture sites involved were often at substantial risk of failure. These parametric model results underscore the importance of retaining or robustly repairing capsular structures in total hip arthroplasty, in order to maximize overall construct stability.
Total hip arthroplasty; hip capsule; finite element analysis; suture failure
Biological soft tissues and cells may be subjected to mechanical as well as chemical (osmotic) loading under their natural physiological environment or various experimental conditions. The interaction of mechanical and chemical effects may be very significant under some of these conditions, yet the highly nonlinear nature of the set of governing equations describing these mechanisms poses a challenge for the modeling of such phenomena. This study formulated and implemented a finite element algorithm for analyzing mechano-chemical events in neutral deformable porous media under finite deformation. The algorithm employed the framework of mixture theory to model the porous permeable solid matrix and interstitial fluid, where the fluid consists of a mixture of solvent and solute. A special emphasis was placed on solute-solid matrix interactions, such as solute exclusion from a fraction of the matrix pore space (solubility) and frictional momentum exchange that produces solute hindrance and pumping under certain dynamic loading conditions. The finite element formulation implemented full coupling of mechanical and chemical effects, providing a framework where material properties and response functions may depend on solid matrix strain as well as solute concentration. The implementation was validated using selected canonical problems for which analytical or alternative numerical solutions exist. This finite element code includes a number of unique features that enhance the modeling of mechano-chemical phenomena in biological tissues. The code is available in the public domain, open source finite element program FEBio (http://mrl.sci.utah.edu/software).
The relatively high incidence of labral tears among patients presenting with hip pain suggests that the acetabular labrum is often subjected to injurious loading in vivo. However, it is unclear whether the labrum participates in load transfer across the joint during activities of daily living. This study examined the role of the acetabular labrum in load transfer for hips with normal acetabular geometry and acetabular dysplasia using subject-specific finite element analysis. Models were generated from volumetric CT data and analyzed with and without the labrum during activities of daily living. The labrum in the dysplastic model supported 4-11% of the total load transferred across the joint, while the labrum in the normal model supported only 1-2% of the total load. Despite the increased load transferred to the acetabular cartilage in simulations without the labrum, there were minimal differences in cartilage contact stresses. This was because the load supported by the cartilage correlated to the cartilage contact area. A higher percentage of load was transferred to the labrum in the dysplastic model because the femoral head achieved equilibrium near the lateral edge of the acetabulum. The results of this study suggest that the labrum plays a larger role in load transfer and joint stability in hips with acetabular dysplasia than in hips with normal acetabular geometry.
acetabular labrum; hip; cartilage mechanics; finite element; dysplasia
Studies of behavioral weight loss intervention in psychotic patients are sparse and its efficacy compared to other obese patients is unknown. Therefore, we compared the effect of a cognitive-behavioral weight loss intervention in obese subjects with psychotic disorders, other psychiatric diagnoses and without psychiatric disorders.
12-month, naturalistic study of weekly group or individual cognitive-behavioral weight management in 222 consecutively enrolled obese patients (body mass index (BMI):43.7±9.6) with psychotic-spectrum disorders (PSD, n=47), other psychiatric disorders (OPD, n=49) and no psychiatric disorder (NPD, n=126).
PSD patients had greater treatment persistence (48.9%) and longer treatment duration (8.7±4.4 months) than OPD (22.4%, 5.4±4.3 months) and NPD (22.2%, 4.9±4.7 months) patients (p’s<.01, number-needed-to-treat (NNT)=3). In last-observation-carried-forward analyses, PSD patients had greater percent baseline weight loss at 12 months (5.1±9.3%) than OPD and NPD patients (2.7±5.5% and 2.4±6.3%); greater percent BMI loss at 9 and 12 months than both groups (p’s<.05), and greater BMI loss at 9 months (2.1±3.5) and 12 months (2.3±4.1) than NPD patients (1.1±2.3 and 1.2±2.4). Furthermore, weight loss ≥5%, occurred in 42.6% of PSD patients vs. 18.4% and 23.0% in OPD and NPD patients (p’s<.01, NNT=5 and 6). The strongest weight loss predictor was treatment duration (β=.51–.54, p<.001). Attrition was predicted by NPD (p=.001) and OPD group status (p=.036), lower proportion of group sessions (p=.002), higher depression (p=.028), and lower baseline BMI (p=0.030).
Psychosis-spectrum disorder patients had greater weight loss than other obese patients. Non-adherence and depression should be targeted to enhance weight loss success.
Obesity; Weight Management Program; Weight Loss; Attrition; Psychosis
We prospectively collected clinical data during the period 2001–2006 on 60 hips with symptomatic femoroacetabular impingement that had radiographic evidence of acetabular retroversion defined as a crossover sign on an adequate anteroposterior radiograph or retroversion on magnetic resonance imaging or computed tomography. Our treatment algorithm for acetabular retroversion used measurements of acetabular coverage (lateral center edge angle and the posterior wall sign) and condition of acetabular cartilage to direct treatment of acetabular retroversion. The algorithm directed the surgeon to perform a periacetabular-osteotomy (PAO) in 30 hips and in 30 hips a surgical-dislocation and osteochondroplasty (SDO) of the femoral head-neck junction and acetabular rim. HHS and Tönnis radiographic grading were collected preoperatively and at latest followup. The HHS improved from 52 to 90 in the hips treated with SDO and 72 to 91 in the hips treated with PAO, with an overall survivorship of 96% at four years. Patient follow-up averaged 46 months (range 24–75). Elimination of the crossover sign and correction of the posterior wall sign occurred in over 90% of all patients when present. The results indicate that hips with acetabular retroversion, deficient posterior and/or lateral acetabular coverage and intact hyaline cartilage can be effectively treated with acetabular reorientation while retroverted hips with anterior over-coverage but sufficient posterior coverage are effectively treated with osteochondroplasty of the acetabulum and proximal femur.
Background and purpose
Acetabular retroversion may result in anterior acetabular over-coverage and posterior deficiency. It is unclear how standard radiographic measures of retroversion relate to measurements from 3D models, generated from volumetric CT data. We sought to: (1) compare 2D radiographic measurements between patients with acetabular retroversion and normal control subjects, (2) compare 3D measurements of total and regional femoral head coverage between patients and controls, and (3) quantify relationships between radiographic measurements of acetabular retroversion to total and regional coverage of the femoral head.
Patients and methods
For 16 patients and 18 controls we measured the extrusion index, crossover ratio, acetabular angle, acetabular index, lateral center edge angle, and a new measurement termed the “posterior wall distance”. 3D femoral coverage was determined from volumetric CT data using objectively defined acetabular rim projections, head-neck junctions, and 4 anatomic regions. For radiographic measurements, intra-observer and inter-observer reliabilities were evaluated and associations between 2D radiographic and 3D model-based measures were determined.
Compared to control subjects, patients with acetabular retroversion had a negative posterior wall distance, increased extrusion index, and smaller lateral center edge angle. Differences in the acetabular index between groups approached statistical significance. The acetabular angle was similar between groups. Acetabular retroversion was associated with a slight but statistically significant increase in anterior acetabular coverage, especially in the anterolateral region. Retroverted hips had substantially less posterior coverage, especially in the posterolateral region.
We found that a number of 2D radiographic measures of acetabular morphology were correlated with 3D model-based measures of total and regional femoral head coverage. These correlations may be used to assist in the diagnosis of retroversion and for preoperative planning.
Computational techniques and software for the analysis of problems in mechanics have naturally moved from their origins in the traditional engineering disciplines to the study of cell, tissue and organ biomechanics. Increasingly complex models have been developed to describe and predict the mechanical behavior of such biological systems. While the availability of advanced computational tools has led to exciting research advances in the field, the utility of these models is often the subject of criticism due to inadequate model verification and validation. The objective of this review is to present the concepts of verification, validation and sensitivity studies with regard to the construction, analysis and interpretation of models in computational biomechanics. Specific examples from the field are discussed. It is hoped that this review will serve as a guide to the use of verification and validation principles in the field of computational biomechanics, thereby improving the peer acceptance of studies that use computational modeling techniques.
Verification; Validation; Sensitivity Studies; Computational Modeling; Biomechanics; Review
Porous-permeable tissues have often been modeled using porous media theories such as the biphasic theory. This study examines the equivalence of the short-time biphasic and incompressible elastic responses for arbitrary deformations and constitutive relations from first principles. This equivalence is illustrated in problems of unconfined compression of a disk, and of articular contact under finite deformation, using two different constitutive relations for the solid matrix of cartilage, one of which accounts for the large disparity observed between the tensile and compressive moduli in this tissue. Demonstrating this equivalence under general conditions provides a rationale for using available finite element codes for incompressible elastic materials as a practical substitute for biphasic analyses, so long as only the short-time biphasic response is sought. In practice, an incompressible elastic analysis is representative of a biphasic analysis over the short-term response
δt≪Δ2/‖C4‖||K||, where Δ is a characteristic dimension,
C4 is the elasticity tensor and K is the hydraulic permeability tensor of the solid matrix. Certain notes of caution are provided with regard to implementation issues, particularly when finite element formulations of incompressible elasticity employ an uncoupled strain energy function consisting of additive deviatoric and volumetric components.
The anterior-inferior glenohumeral capsule is the primary passive stabilizer to the glenohumeral joint during anterior dislocation. Physical examinations following dislocation are crucial for proper diagnosis of capsule pathology; however, they are not standardized for joint position which may lead to misdiagnoses and poor outcomes. To suggest joint positions for physical examinations where the stability provided by the capsule may be consistent among patients, the objective of this study was to evaluate the distribution of maximum principal strain on the anterior-inferior capsule using two validated subject-specific finite element models of the glenohumeral joint at clinically relevant joint positions. The joint positions with 25 N anterior load applied at 60° of glenohumeral abduction and 10°, 20°, 30° and 40° of external rotation resulted in distributions of strain that were similar between shoulders (r2 ≥ 0.7). Furthermore, those positions with 20° to 40° of external rotation resulted in capsule strains on the glenoid side of the anterior band of the inferior glenohumeral ligament that were significantly greater than in all other capsule regions. These findings suggest that anterior stability provided by the anterior-inferior capsule may be consistent among subjects at joint positions with 60° of glenohumeral abduction and a mid-range (20° to 40°) of external rotation, and that the glenoid side has the greatest contribution to stability at these joint positions. Therefore, it may be possible to establish standard joint positions for physical examinations that clinicians can use to effectively diagnose pathology in the anterior-inferior capsule following dislocation and lead to improved outcomes.
shoulder; glenohumeral joint; finite element models; ligament; strain
The structural organization of biological tissues and cells often produces anisotropic transport properties. These tissues may also undergo large deformations under normal function, potentially inducing further anisotropy. A general framework for formulating constitutive relations for anisotropic transport properties under finite deformation is lacking in the literature. This study presents an approach based on representation theorems for symmetric tensor-valued functions and provides conditions to enforce positive semi-definiteness of the permeability or diffusivity tensor. Formulations are presented which describe materials that are orthotropic, transversely isotropic, or isotropic in the reference state, and where large strains induce greater anisotropy. Strain-induced anisotropy of the permeability of a solid-fluid mixture is illustrated for finite torsion of a cylinder subjected to axial permeation. It is shown that, in general, torsion can produce a helical flow pattern, rather than the rectilinear pattern observed when adopting a more specialized, unconditionally isotropic spatial permeability tensor commonly used in biomechanics. The general formulation presented in this study can produce both affine and non-affine reorientation of the preferred directions of material symmetry with strain, depending on the choice of material functions. This study addresses a need in the biomechanics literature by providing guidelines and formulations for anisotropic strain-dependent transport properties in porous-deformable media undergoing large deformations.
Next-generation sequencing (NGS) enables the highly sensitive measurement of whole transcriptomes. We report the first application to our knowledge of this technology to the analysis of RNA from a CD4+ T cell line infected with intact HIV. We sequenced the total mRNA from infected cells and detected differences in the expression of both host and viral mRNA. Viral reads represented a large portion of the total mapped sequencing reads: approximately 20% at 12 h postinfection (hpi) and 40% at 24 hpi. We also detected a small but significant suppression of T cell activation-related genes at 12 hpi. This suppression persisted and expanded by 24 hpi, providing new possible markers of virus-induced T cell cytopathology. By 24 hpi, the expression of over 50% of detectable host loci was also altered, indicating widespread alteration of host processes, including RNA processing, splicing, and transport to an extent not previously reported. In addition, next-generation sequencing provided insights into alternative viral RNA splice events and the expression of noncoding RNAs, including microRNA host genes.
Recent advances in sequencing technology now allow the measurement of effectively all the RNA in a cell. This approach is especially useful for studying models of virus infection, as it allows the simultaneous measurement of both host and viral RNA. Using next-generation sequencing (NGS), we measured changes in total mRNA from a HIV-infected T cell line. To our knowledge, this is the first application of this technology to the investigation of HIV-host interactions involving intact HIV. We directly measured the amount of viral mRNA in infected cells and detected novel viral RNA splice variants and changes in the host expression of noncoding RNA species. We also detected small changes in T cell activation and other host processes during the early stages of viral replication that increased near the peak of viral replication, providing new candidate biomarkers of T cell death.
Dermatan and chondroitin sulfate glycosaminoglycans (GAGs) comprise over 90% of the GAG content in ligament. Studies of their mechanical contribution to soft tissues have reported conflicting results. Measuring the transient compressive response and biphasic material parameters of the tissue may elucidate the contributions of GAGs to the viscoelastic response to deformation. The hypotheses of the current study were that digestion of sulfated GAGs would decrease compressive stress and aggregate modulus while increasing the permeability of porcine medial collateral ligament (MCL). Confined compression stress relaxation experiments were carried out on porcine MCL and tissue treated with chondroitinase ABC (ChABC). Results were fit to a biphasic constitutive model to derive permeability and aggregate modulus. Bovine articular cartilage was used as a benchmark tissue to verify that the apparatus provided reliable results. GAG digestion removed up to 88% of sulfated GAGs from the ligament. Removal of sulfated GAGs increased the permeability of porcine MCL nearly 6-fold versus control tissues. Peak stress decreased significantly. Bovine articular cartilage exhibited the typical reduction of GAG content and resultant decreases in stress and modulus and increases in permeability with ChABC digestion. Given the relatively small amount of GAG in ligament (<1% of tissue dry weight) and the significant change in peak stress and permeability upon removal of GAGs, sulfated GAGs may play a significant role in maintaining the apposition of collagen fibrils in the transverse direction, thus supporting dynamic compressive loads experienced by the ligament during complex joint motion.
ligament; permeability; glycosaminoglycan; chondroitinase; stress relaxation
This study formulates and implements a finite element contact algorithm for solid-fluid (biphasic) mixtures, accommodating both finite deformation and sliding. The finite element source code is made available to the general public.
The algorithm uses a penalty method regularized with an augmented Lagrangian method to enforce the continuity of contact traction and normal component of fluid flux across the contact interface. The formulation addresses the need to automatically enforce free-draining conditions outside of the contact interface. The formulation addresses the need to automatically enforce free-draining conditions outside of the contact interface.
The accuracy of the implementation is verified using contact problems for which exact solutions are obtained by alternative analyses. Illustrations are also provided that demonstrate large deformations and sliding under configurations relevant to biomechanical applications such as articular contact.
This study addresses an important computational need in the biomechanics of porous-permeable soft tissues. Placing the source code in the public domain provides a useful resource to the biomechanics community.
Computational models may have the ability to quantify the relationship between hip morphology, cartilage mechanics and osteoarthritis. Most models have assumed the hip joint to be a perfect ball and socket joint and have neglected deformation at the interface between bone/cartilage. The objective of this study was to analyze finite element (FE) models of hip cartilage mechanics with varying degrees of simplified geometry and a model with a rigid bone material assumption to elucidate the effects on predictions of cartilage stress. A previously validated subject-specific FE model of a cadaveric hip joint was used as the basis for the models. Geometry for the bone/cartilage interface was either: 1) subject-specific (i.e. irregular), 2) spherical, or 3) a rotational conchoid. Cartilage was assigned either a varying (irregular) or constant thickness (smoothed). Loading conditions simulated walking, stair climbing and descending stairs. FE predictions of contact stress for the simplified models were compared with predictions from the subject-specific model. Both spheres and conchoids provided a good approximation of native hip joint geometry (average fitting error ~0.5 mm). However, models with spherical/conchoid bone geometry and smoothed articulating cartilage surfaces grossly underestimated peak and average contact pressures (50% and 25% lower, respectively) and overestimated contact area when compared to the subject-specific FE model. Models incorporating subject-specific bone geometry with smoothed articulating cartilage also underestimated pressures and predicted evenly distributed patterns of contact. The model with rigid bones predicted much higher pressures than the subject-specific model with deformable bones. The results demonstrate that simplifications to the geometry of the bone/cartilage interface, cartilage surface and bone material properties can have a dramatic effect on the predicted magnitude and distribution of cartilage contact pressures in the hip joint.
Hip; Finite Element; Biomechanics; Sphere; Conchoid; Boundary Conditions; Cartilage Pressures
Experimental measurements of the Poisson’s ratio in tendon and ligament tissue greatly exceed the isotropic limit of 0.5. This is indicative of volume loss during tensile loading. The microstructural origin of the large Poisson’s ratios is unknown. It was hypothesized that a helical organization of fibrils within a fiber would result in a large Poisson’s ratio in ligaments and tendons, and that this helical organization would be compatible with the crimped nature of these tissues, thus modeling their classic nonlinear stress strain behavior. Micromechanical finite element models were constructed to represent crimped fibers with a super helical organization, composed of fibrils embedded within a matrix material. A homogenization procedure was performed to determine both the effective Poisson’s ratio and the Poisson function. The results showed that helical fibril organization within a crimped fiber was capable of simultaneously predicting large Poisson’s ratios and the nonlinear stress strain behavior seen experimentally. Parametric studies revealed that the predicted Poisson’s ratio was strongly dependent on the helical pitch, crimp angle and the material coefficients. The results indicated that, for physiologically relevant parameters, the models were capable of predicting the large Poisson’s ratios seen experimentally. It was concluded that helical organization within a crimped fiber can produce both the characteristic nonlinear stress strain behavior and large Poisson’s ratios, while fiber crimp alone could only account for the nonlinear stress-strain behavior.
Ligament; Micromechanical; Poisson’s Ratio; Finite Element; Helical; Fiber; Tendon
Effective tissue prevascularization depends on new vessel growth and subsequent progression of neovessels into a stable microcirculation. Isolated microvessel fragments in a collagen-based microvascular construct (MVC) spontaneously undergo angiogenesis in static conditions in vitro but form a new microcirculation only when implanted in vivo. We have designed a bioreactor, the dynamic in vitro perfusion (DIP) chamber, to culture MVCs in vitro with perfusion. By altering bioreactor circulation, microvessel fragments in the DIP chamber either maintained stable, nonsprouting, patent vessel morphologies or sprouted endothelial neovessels that extended out into the surrounding collagen matrix (i.e., angiogenesis), yielding networks of neovessels within the MVC. Neovessels formed in regions of the construct predicted by simulation models to have the steepest gradients in oxygen levels and expressed hypoxia inducible factor-1α. By altering circulation conditions in the DIP chamber, we can control, possibly by modulating hypoxic stress, prevascularizing activity in vitro.