Microarchitectural Features Research Articles

Bone histomorphometric changes in children with rheumatic disorders on chronic glucocorticoids.

BackgroundRheumatic diseases are associated with an increased fracture risk. The tissue level characteristics of the bone involvement in children have not been well elucidated. Our objectives were to describe the bone micro-architectural characteristics in children with rheumatic diseases on chronic glucocorticoids, and to determine associations between micro-architectural findings with clinical and radiological variables.MethodsChildren on chronic glucocorticoids for an underlying rheumatic disease were referred for evaluation of bone fragility given the presence of vertebral compression fractures. A trans-iliac bone biopsy was performed as part of the clinical assessment. Histomorphometric analysis and quantitative backscattered electron imaging (qBSE) of the biopsy samples were undertaken.ResultsData of 15 children (14.0 ± 3.2 years) with a duration of glucocorticoid exposure of 6.2 ± 4.1 years and average prednisone dose of 14.1 ± 6.2 mg/m2/day were assessed. Histomorphometric analyses demonstrated significant decrease in trabecular thickness (p = 0.01), osteoid thickness (p < 0.01), osteoblast surface (p = 0.02) and increase in trabecular separation (p = 0.04) compared to published age-matched normative data. Severity of the trabecular deficit was correlated to glucocorticoid dose, height and body mass index Z score, but not bone mineral density or measures of disease activity. Using qBSE to measure bone mineralization, the subjects were shown to have a heterogeneous and hypermineralized profile, with higher cumulative glucocorticoid dose being associated with greater mineralization (p < 0.01).ConclusionsIn children with rheumatic diseases presenting with vertebral fractures, there is evidence of abnormal bone matrix mineralization and impairments of bone micro-architecture that correlate to glucocorticoid dose.

Calcific Aortic Valve Disease Is Associated with Layer-Specific Alterations in Collagen Architecture.

Disorganization of the valve extracellular matrix (ECM) is a hallmark of calcific aortic valve disease (CAVD). However, while microarchitectural features of the ECM can strongly influence the biological and mechanical behavior of tissues, little is known about the ECM microarchitecture in CAVD. In this work, we apply advanced imaging techniques to quantify spatially heterogeneous changes in collagen microarchitecture in CAVD. Human aortic valves were obtained from individuals between 50 and 75 years old with no evidence of valvular disease (healthy) and individuals who underwent valve replacement surgery due to severe stenosis (diseased). Second Harmonic Generation microscopy and subsequent image quantification revealed layer-specific changes in fiber characteristics in healthy and diseased valves. Specifically, the majority of collagen fiber changes in CAVD were found to occur in the spongiosa, where collagen fiber number increased by over 2-fold, and fiber width and density also significantly increased. Relatively few fibrillar changes occurred in the fibrosa in CAVD, where fibers became significantly shorter, but did not otherwise change in terms of number, width, density, or alignment. Immunohistochemical staining for lysyl oxidase showed localized increased expression in the diseased fibrosa. These findings reveal a more complex picture of valvular collagen enrichment and arrangement in CAVD than has previously been described using traditional analysis methods. Changes in fiber architecture may play a role in regulating the pathobiological events and mechanical properties of valves during CAVD. Additionally, characterization of the ECM microarchitecture can inform the design of fibrous scaffolds for heart valve tissue engineering.

The roles of architecture and estrogen depletion in microdamage risk in trabecular bone

Bone quantity, or density, has insufficient power to discriminate fracture risk in individuals. Additional measures of bone quality, such as microarchitectural characteristics and bone tissue properties, including the presence of damage, may improve the diagnosis of fracture risk. Microdamage and microarchitecture are two aspects of trabecular bone quality that are interdependent, with several microarchitectural changes strongly correlated to damage risk after compensating for bone density. This study aimed to delineate the effects of microarchitecture and estrogen depletion on microdamage susceptibility in trabecular bone using an ovariectomized sheep model to mimic post-menopausal osteoporosis. The propensity for microdamage formation in trabecular bone of the distal femur was studied using a sequence of compressive and torsional overloads. Ovariectomy had only minor effects on the microarchitecture at this anatomic site. Microdamage was correlated to bone volume fraction and structure model index (SMI), and ovariectomy increased the sensitivity to these parameters. The latter may be due to either increased resorption cavities acting as stress concentrations or to altered bone tissue properties. Pre-existing damage was also correlated to new damage formation. However, sequential loading primarily generated new cracks as opposed to propagating existing cracks, suggesting that pre-existing microdamage contributes to further damage of bone by shifting load bearing to previously undamaged trabeculae, which are subsequently damaged. The transition from plate-like to rod-like trabeculae, indicated by SMI, dictates this shift, and may be a hallmark of bone that is already predisposed to accruing greater levels of damage through compromised microarchitecture.

Scaffold microstructure effects on functional and mechanical performance: Integration of theoretical and experimental approaches for bone tissue engineering applications

The really nontrivial goal of tissue engineering is combining all scaffold micro-architectural features, affecting both fluid-dynamical and mechanical performance, to obtain a fully functional implant.In this work we identified an optimal geometrical pattern for bone tissue engineering applications, best balancing several graft needs which correspond to competing design goals. In particular, we investigated the occurred changes in graft behavior by varying pore size (300μm, 600μm, 900μm), interpore distance (equal to pore size or 300μm fixed) and pores interconnection (absent, 45°-oriented, 90°-oriented). Mathematical considerations and Computational Fluid Dynamics (CFD) tools, here combined in a complete theoretical model, were carried out to this aim.Poly-lactic acid (PLA) based samples were realized by 3D printing, basing on the modeled architectures. A collagen (COL) coating was also realized on grafts surface and the interaction between PLA and COL, besides the protein contribution to graft bioactivity, was evaluated.Scaffolds were extensively characterized; human articular cells were used to test their biocompatibility and to evaluate the theoretical model predictions.Grafts fulfilled both the chemical and physical requirements. Finally, a good agreement was found between the theoretical model predictions and the experimental data, making these prototypes good candidates for bone graft replacements.

VThreads: A novel VLIW chip multiprocessor with hardware-assisted PThreads

We discuss VThreads, a novel VLIW CMP with hardware-assisted shared-memory Thread support. VThreads supports Instruction Level Parallelism via static multiple-issue and Thread Level Parallelism via hardware-assisted POSIX Threads along with extensive customization. It allows the instantiation of tightly-coupled streaming accelerators and supports up to 7-address Multiple-Input, Multiple-Output instruction extensions. VThreads is designed in technology-independent Register-Transfer-Level VHDL and prototyped on 40 nm and 28 nm Field-Programmable gate arrays. It was evaluated against a PThreads-based multiprocessor based on the Sparc-V8 ISA. On a 65 nm ASIC implementation VThreads achieves up to x7.2 performance increase on synthetic benchmarks, x5 on a parallel Mandelbrot implementation, 66% better on a threaded JPEG implementation, 79% better on an edge-detection benchmark and ∼13% improvement on DES compared to the Leon3MP CMP. In the range of 2 to 8 cores, VThreads demonstrates a post-route (statistical) power reduction between 65% and 57% at an area increase of 1.2%–10% for 1–8 cores, compared to a similarly-configured Leon3MP CMP. This combination of micro-architectural features, scalability, extensibility, hardware support for low-latency PThreads, power efficiency and area make the processor an attractive proposition for low-power, deeply-embedded applications requiring minimum OS support.

COBAYN

The variety of today’s architectures forces programmers to spend a great deal of time porting and tuning application codes across different platforms. Compilers themselves need additional tuning, which has considerable complexity as the standard optimization levels, usually designed for the average case and the specific target architecture, often fail to bring the best results. This article proposes COBAYN : Compiler autotuning framework using BAYesian Networks, an approach for a compiler autotuning methodology using machine learning to speed up application performance and to reduce the cost of the compiler optimization phases. The proposed framework is based on the application characterization done dynamically by using independent microarchitecture features and Bayesian networks. The article also presents an evaluation based on using static analysis and hybrid feature collection approaches. In addition, the article compares Bayesian networks with respect to several state-of-the-art machine-learning models. Experiments were carried out on an ARM embedded platform and GCC compiler by considering two benchmark suites with 39 applications. The set of compiler configurations, selected by the model (less than 7% of the search space), demonstrated an application performance speedup of up to 4.6 × on Polybench (1.85 × on average) and 3.1 × on cBench (1.54 × on average) with respect to standard optimization levels. Moreover, the comparison of the proposed technique with (i) random iterative compilation, (ii) machine learning--based iterative compilation, and (iii) noniterative predictive modeling techniques shows, on average, 1.2 × , 1.37 × , and 1.48 × speedup, respectively. Finally, the proposed method demonstrates 4 × and 3 × speedup, respectively, on cBench and Polybench in terms of exploration efficiency given the same quality of the solutions generated by the random iterative compilation model.

A structural finite element model for lamellar unit of aortic media indicates heterogeneous stress field after collagen recruitment

Incorporation of collagen structural information into the study of biomechanical behavior of ascending thoracic aortic (ATA) wall tissue should provide better insight into the pathophysiology of ATA. Structurally motivated constitutive models that include fiber dispersion and recruitment can successfully capture overall mechanical response of the arterial wall tissue. However, these models cannot examine local microarchitectural features of the collagen network, such as the effect of fiber disruptions and interaction between fibrous and non-fibrous components, which may influence emergent biomechanical properties of the tissue. Motivated by this need, we developed a finite element based three-dimensional structural model of the lamellar units of the ATA media that directly incorporates the collagen fiber microarchitecture. The fiber architecture was computer generated utilizing network features, namely fiber orientation distribution, intersection density and areal concentration, obtained from image analysis of multiphoton microscopy images taken from human aneurysmal ascending thoracic aortic media specimens with bicuspid aortic valve (BAV) phenotype. Our model reproduces the typical J-shaped constitutive response of the aortic wall tissue. We found that the stress state in the non-fibrous matrix was homogeneous until the collagen fibers were recruited, but became highly heterogeneous after that event. The degree of heterogeneity was dependent upon local network architecture with high stresses observed near disrupted fibers. The magnitude of non-fibrous matrix stress at higher stretch levels was negatively correlated with local fiber density. The localized stress concentrations, elucidated by this model, may be a factor in the degenerative changes in aneurysmal ATA tissue.

Bone impairment assessed by HR-pQCT in juvenile-onset systemic lupus erythematosus.

High-resolution peripheral quantitative computed tomography (HR-pQCT) analysis of female juvenile-onset systemic lupus erythematosus (JoSLE) patients revealed trabecular/cortical bone damage and reduced bone strength primarily at the distal radius compared to healthy controls. We demonstrated for the first time that JoSLE patients with vertebral fracture (VF) present trabecular impairment at the distal radius. This study investigated the volumetric bone mineral density (vBMD), microarchitecture, and biomechanical features at the distal radius and tibia using HR-pQCT and laboratory bone markers in JoSLE patients compared to controls to determine whether this method discriminates JoSLE patients with or without VF. We compared 56 female JoSLE patients to age- and Tanner-matched healthy controls. HR-pQCT was performed at the distal radius and tibia. Serum levels of the amino-terminal pro-peptide of type I collagen, the C-terminal telopeptide of type I collagen, intact parathormone, sclerostin, and 25-hydroxyvitamin D (25OHD) were evaluated. VFs were analyzed using VFA-dual-energy X-ray absorptiometry (DXA) (Genant's method). Reduced density and strength parameters and microarchitecture alterations of cortical and trabecular bones were observed in JoSLE patients compared to controls, primarily at the distal radius (p < 0.05). Patients with VF exhibited a significant decrease in trabecular bone parameters solely at the distal radius (Total.BMD, p = 0.034; Trabecular.BMD [Tb.BMD], p = 0.034; bone volume (BV)/trabecular volume (TV), p = 0.034; apparent modulus, p = 0.039) and higher scores for disease damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI), p = 0.002). Bone metabolism markers were similar in all groups. Logistic regression analysis of parameters that were significant in univariate analysis revealed that Tb.BMD (OR 0.98, 95% CI 0.95-0.99, p = 0.039) and SLICC/ACR-DI (OR 7.37, 95% CI 1.75-30.97, p = 0.006) were independent risk factors for VF. In conclusion, this study is the first demonstration of bone microstructure and strength deficits in JoSLE patients, particularly at the distal radius. Our results demonstrated that VF was associated with trabecular radius alteration and emphasized the potential detrimental effect of disease damage on this condition.

Optical coherence tomography for differentiation of parathyroid gland tissue

Optical coherence tomography (OCT) is a high-resolution imaging technique that allows the identification of microarchitectural features in real-time. Can OCT be used to differentiate parathyroid tissue from other cervical tissue entities? All investigations were carried out during cervical operations. Initially, ex vivo images were analyzed to define morphological imaging criteria for each tissue entity. These criteria were used to evaluate a first series of ex vivo images. In a second phase the practicability of the technique was investigated in vivo and in the third phase backscattering intensity measurements were analyzed employing linear discriminant analysis (LDA). In the ex vivo series parathyroid tissue could be differentiated from other tissue entities with a sensitivity and specificity of 84 % and 94 %, respectively. Parathyroid tissue was correctly identified in the in vivo series in only 69.2 %. The analysis of backscattering intensity profiles employing LDA reliably distinguished between the different tissue types. The OCT images displayed typical characteristics for each tissue entity. Due to technical problems in handling the probe the in vivo OCT images were of much poorer quality. Backscattering intensity measurements illustrated that OCT images provide an individual profile for each tissue entity independent of the defined morphological assessment criteria. The results show that OCT is fundamentally suitable for intraoperative differentiation of tissues.

Designing Area Optimized Application-Specific Network-On-Chip Architectures while Providing Hard QoS Guarantees

With the increase of transistors' density, popularity of System on Chip (SoC) has increased exponentially. As a communication module for SoC, Network on Chip (NoC) framework has been adapted as its backbone. In this paper, we propose a methodology for designing area-optimized application specific NoC while providing hard Quality of Service (QoS) guarantees for real time flows. The novelty of the proposed system lies in derivation of a Mixed Integer Linear Programming model which is then used to generate a resource optimal Network on Chip (NoC) topology and architecture while considering traffic and QoS requirements. We also present the micro-architectural design features used for enabling traffic and latency guarantees and discuss how the solution adapts for dynamic variations in the application traffic. The paper highlights the effectiveness of proposed method by generating resource efficient NoC solutions for both industrial and benchmark applications. The area-optimized results are generated in few seconds by proposed technique, without resorting to heuristics, even for an application with 48 traffic flows.

Multi-level femoral morphology and mechanical properties of rats of different ages

A macro–micro–nano–multi-level study was conducted to explore age-related structural and mechanical properties of bone, as well as the effects of aging on bone properties. A total of 70 male Wistar rats were used, ranging in the ages of 1, 3, 5, 7, 9, 11, 14, 15, 16, and 17months (n=7/age group). After micro-computed tomography (CT) scanning, longitudinal cortical bone specimens with a length of 5mm were cut along the femoral shaft axis from left femur shafts for mechanical testing, and the cross-sectional areas were measured. The macro-mechanical properties obtained in mechanical testing and microarchitecture parameters measured by micro-CT were significantly correlated with the animal age (r2=0.96, p<0.001). Scanning electron microscopy was used for detecting the microarchitecture features of the fractured surfaces, which exhibited age-related plate-fibrous-mixed fibrous-plate texture, resulting in changes in macro-mechanical properties (r2>0.90, p<0.001). The mineral phase of the left femoral shaft and head was analyzed by atomic force microscopy. Longitudinal and transverse trabecular bone tissues, as well as longitudinal cortical bone tissue, were used for nanoindentation test, and the chemical composition was evaluated by quantitative chemical analyses. The correlations between mineral content and bone material properties (i.e., elastic properties of the bone tissue and size and roughness of bone mineral grains) were highly significant (r>0.95, p<0.001). Multi-level femur morphology, mechanical property, and mineral content were significantly correlated with the animal age. The correlations between bone mineral content and bone material morphological and mechanical properties may partly explain the increase in bone fragility with aging, which will provide a theoretical basis for the investigation of age-related bone properties in clinics.

Strong similarities in the creep and damage behaviour of a synthetic bone model compared to human trabecular bone under compressive cyclic loading

Understanding the failure modes which instigate vertebral collapse requires the determination of trabecular bone fatigue properties, since many of these fractures are observed clinically without any preceding overload event. Alternatives to biological bone tissue for in-vitro fatigue studies are available in the form of commercially available open cell polyurethane foams. These test surrogates offer particular advantages compared to biological tissue such as a controllable architecture and greater uniformity. The present study provides a critical evaluation of these models as a surrogate to human trabecular bone tissue for the study of vertebral augmentation treatments such as balloon kyphoplasty. The results of this study show that while statistically significant differences were observed for the damage response of the two materials, both share a similar three phase modulus reduction over their life span with complete failure rapidly ensuing at damage levels above 30%. No significant differences were observed for creep accumulation properties, with greater than 50% of creep strains being accumulated during the first quarter of the life span for both materials. A significant power law relationship was identified between damage accumulation rate and cycles to failure for the synthetic bone model along with comparable microarchitectural features and a hierarchical composite structure consistent with biological bone. These findings illustrate that synthetic bone models offer potential as a surrogate for trabecular bone to an extent that warrants a full validation study to define boundaries of use which compliment traditional tests using biological bone.

Significant bone microarchitecture impairment in premenopausal women with active celiac disease

Patients with active celiac disease (CD) are more likely to have osteoporosis and increased risk of fractures. High-resolution peripheral quantitative computed tomography (HR-pQCT) permits three-dimensional exploration of bone microarchitectural characteristics measuring separately cortical and trabecular compartments, and giving a more profound insight into bone disease pathophysiology and fracture. We aimed to determine the volumetric and microarchitectural characteristics of peripheral bones—distal radius and tibia—in an adult premenopausal cohort with active CD assessed at diagnosis. We prospectively enrolled 31 consecutive premenopausal women with newly diagnosed CD (median age 29years, range: 18–49) and 22 healthy women of similar age (median age 30years, range 21–41) and body mass index. Compared with controls, peripheral bones of CD patients were significantly lower in terms of total volumetric density mg/cm3 (mean±SD: 274.7±51.7 vs. 324.7±45.8, p 0.0006 at the radius; 264.4±48.7 vs. 307±40.7, p 0.002 at the tibia), trabecular density mg/cm3 (118.6±31.5 vs. 161.9±33.6, p<0.0001 at the radius; 127.9±28.7 vs. 157.6±15.6, p<0.0001 at the tibia); bone volume/trabecular volume ratio % (9.9±2.6 vs. 13.5±2.8, p<0.0001 at the radius; 10.6±2.4 vs. 13.1±1.3, p<0.0001 at the tibia); number of trabeculae 1/mm (1.69±0.27 vs. 1.89±0.26, p 0.009 at the radius; 1.53±0.32 vs. 1.80±0.26, p 0.002 at the tibia); and trabecular thickness mm (0.058±0.010 vs. 0.071±0.008, p<0.0001 at the radius with no significant difference at the tibia). Cortical density was significantly lower in both regions (D comp mg/cm3 860±57.2 vs. 893.9±43, p 0.02; 902.7±48.7 vs. 932.6±32.6, p 0.01 in radius and tibia respectively). Although cortical thickness was lower in CD patients, it failed to show any significant inter-group difference (a—8% decay with p 0.11 in both bones). Patients with symptomatic CD (n=22) had a greater bone microarchitectural deficit than those with subclinical CD. HR-pQCT was used to successfully identify significant deterioration in the microarchitecture of trabecular and cortical compartments of peripheral bones. Impairment was characterized by lower trabecular number and thickness—which increased trabecular network heterogeneity—and lower cortical density and thickness. In the prospective follow-up of this group of patients we expect to be able to assess whether bone microarchitecture recovers and to what extend after gluten-free diet.

Micro-Architectural Analysis of Time-Driven Cache Attacks: Quest for the Ideal Implementation

Time-driven attacks on the data cache are a lethal form of cryptanalytic attacks for block-ciphers implemented with look-up tables. The difference of means (DOM) observed in the execution time of a block cipher is often used as a distinguisher to glean information about the secret key. The root cause for the distinguisher to work has long been attributed to the number of cache-misses that occur during the encryption. In this paper, we show that micro-architectural acceleration features in cache memories that are used to reduce miss-penalty (such as pipelining, parallelism, out-of-order, and non-blocking memory accesses) contribute significantly to the leakage. We develop a framework to analyze the DOM distinguisher considering architectural as well as micro-architectural acceleration components in the cache memory. Our findings, which are experimentally verified, show that the two contributing leakage factors (namely the number of cache misses and the micro-architectural acceleration features) affect the DOM in opposite directions. One leakage source results in a positive DOM while the other causes a negative DOM. This opposing characteristic of the leakages makes it feasible to implement block ciphers in a way such that the two leakages cancel each other, thus leading to implementations with higher resistance against time-driven cache-attacks.

Always-on Vision Processing Unit for Mobile Applications

Myriad 2 is a multicore, always-on system on chip that supports computational imaging and visual awareness for mobile, wearable, and embedded applications. The vision processing unit incorporates parallelism, instruction set architecture, and microarchitectural features to provide highly sustainable performance efficiency across a range of computationalImaging and computer vision applications, including those with low latency requirements on the order of milliseconds.

Studying Optimal Spilling in the Light of SSA

Recent developments in register allocation, mostly linked to static single assignment (SSA) form, have shown the benefits of decoupling the problem in two phases: a first spilling phase places load and store instructions so that the register pressure at all program points is small enough, and a second assignment and coalescing phase maps the variables to physical registers and reduces the number of move instructions among registers. This article focuses on the first phase, for which many open questions remain: in particular, we study the notion of optimal spilling (what can be expressed?) and the impact of SSA form (does it help?). To identify the important features for optimal spilling on load-store architectures, we develop a new integer linear programming formulation, more accurate and expressive than previous approaches. Among other features, we can express SSA ϕ-functions, memory-to-memory copies, and the fact that a value can be stored simultaneously in a register and in memory. Based on this formulation, we present a thorough analysis of the results obtained for the SPECINT 2000 and EEMBC 1.1 benchmarks, from which we draw, among others, the following conclusions: (1) rematerialization is extremely important; (2) SSA complicates the formulation of optimal spilling, especially because of memory coalescing when the code is not in conventional SSA (CSSA); (3) microarchitectural features are significant and thus have to be accounted for; and (4) significant savings can be obtained in terms of static spill costs, cache miss rates, and dynamic instruction counts.

Measuring Microarchitectural Details of Multi- and Many-Core Memory Systems through Microbenchmarking

As multicore and many-core architectures evolve, their memory systems are becoming increasingly more complex. To bridge the latency and bandwidth gap between the processor and memory, they often use a mix of multilevel private/shared caches that are either blocking or nonblocking and are connected by high-speed network-on-chip. Moreover, they also incorporate hardware and software prefetching and simultaneous multithreading (SMT) to hide memory latency. On such multi- and many-core systems, to incorporate various memory optimization schemes using compiler optimizations and performance tuning techniques, it is crucial to have microarchitectural details of the target memory system. Unfortunately, such details are often unavailable from vendors, especially for newly released processors. In this article, we propose a novel microbenchmarking methodology based on short elapsed-time events (SETEs) to obtain comprehensive memory microarchitectural details in multi- and many-core processors. This approach requires detailed analysis of potential interfering factors that could affect the intended behavior of such memory systems. We lay out effective guidelines to control and mitigate those interfering factors. Taking the impact of SMT into consideration, our proposed methodology not only can measure traditional cache/memory latency and off-chip bandwidth but also can uncover the details of software and hardware prefetching units not attempted in previous studies. Using the newly released Intel Xeon Phi many-core processor (with in-order cores) as an example, we show how we can use a set of microbenchmarks to determine various microarchitectural features of its memory system (many are undocumented from vendors). To demonstrate the portability and validate the correctness of such a methodology, we use the well-documented Intel Sandy Bridge multicore processor (with out-of-order cores) as another example, where most data are available and can be validated. Moreover, to illustrate the usefulness of the measured data, we do a multistage coordinated data prefetching case study on both Xeon Phi and Sandy Bridge and show that by using the measured data, we can achieve 1.3X and 1.08X performance speedup, respectively, compared to the state-of-the-art Intel ICC compiler. We believe that these measurements also provide useful insights into memory optimization, analysis, and modeling of such multicore and many-core architectures.

Compound K, a Metabolite of Ginsenosides, Attenuates Collagen-induced Arthritis in Mice

Objective Although several ginsenosides have been reported to have anti-arthritic activity, few in vivo studies of the anti-ar-thritic effects of compound K (CK), a major metabolite of ginsenosides, have been conducted. Therefore, we investigated the preventative and therapeutic effects of CK on collagen-induced arthritis (CIA). Methods CK was administered to CIA mice pre-ventively and therapeutically and post-treatment bone microarchitectural characteristics, histopathological changes, and serum levels of anti-collagen antibodies, tumor necrosis factor-α, and interleukin (IL)-17 were investigated. We also examined cytokine production by type II collagen (CII)-stimulated splenocytes and mRNA expression of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinase (TIMP)-1, receptor activator of nuclear factor-κ B ligand (RANKL), and osteoprotegerin (OPG) in the joint tissues. Results CK reduced the severity of CIA preventively and therapeutically (all p＜0.05). Additionally, CK dose-dependently decreased histopathological signs of arthritis and improved microarchitectural characteristics (all p ＜0.05) at 10 to 20 mg/kg/d in CIA mice. CK treatment significantly decreased the serum levels of anti-CII immunoglobulin G (p＜0.01) and the secretion of interferon-γ and IL-2 from stimulated splenocytes (all p＜0.05). Furthermore, MMP-3/TIMP-1 and RANKL/OPG ratios were suppressed in CK treated mice (all p＜0.01). Conclusion CK attenuated CIA via suppression of the humoral immune response and modulation of joint-destructive mediators. These results suggest that CK has therapeutic potential in rheumatoid arthritis.

Automatic Detection of Cortical Bones Haversian Osteonal Boundaries

This work aims to automatically detect cement lines in decalcified cortical bone sections stained with H&E. Employed is a methodology developed previously by the authors and proven to successfully count and disambiguate the micro-architectural features (namely Haversian canals, canaliculi, and osteocyte lacunae) present in the secondary osteons/Haversian system (osteon) of cortical bone. This methodology combines methods typically considered separately, namely pulse coupled neural networks (PCNN), particle swarm optimization (PSO), and adaptive threshold (AT). In lieu of human bone, slides (at 20× magnification) from bovid cortical bone are used in this study as proxy of human bone. Having been characterized, features with same orientation are used to detect the cement line viewed as the next coaxial layer adjacent to the outermost lamella of the osteon. Employed for this purpose are three attributes for each and every micro-sized feature identified in the osteon lamellar system: (1) orientation, (2) size (ellipse perimeter) and (3) Euler number (a topological measure). From a training image, automated parameters for the PCNN network are obtained by forming fitness functions extracted from these attributes. It is found that a 3-way combination of these features attributes yields good representations of the overall osteon boundary (cement line). Near-unity values of classical metrics of quality (precision, sensitivity, specificity, accuracy, and dice) suggest that the segments obtained automatically by the optimized artificial intelligent methodology are of high fidelity as compared with manual tracing. For bench marking, cement lines segmented by k-means did not fare as well. An analysis based on the modified Hausdorff distance (MHD) of the segmented cement lines also testified to the quality of the detected cement lines vis-a-vis the k-means method.

Approaches to Corneal Tissue Engineering: Top-down or Bottom-up?

Tissue engineering creates biological tissues that aim to improve the function of diseased or damaged tissues such as the cornea (the main refractive component of the eye). Traditional tissue engineering strategies employ a “top-down” approach, in which cells are seeded on a polymeric scaffold that they then populate and create the appropriate extracellular matrix (ECM) often with the aid of perfusion, growth factors and/or mechanical stimulation. However, in highly organised tissues, such as the cornea, top-down approaches have difficulty recreating intricate but necessary microstructural features.With the desire to create more complex corneal tissues with features such as anisotropic hierarchical molecular assemblies, appropriate mechanical properties, cell binding motifs and corneal specific morphology, we are developing tissue engineering techniques that are moving away from the traditional top-down approach and instead focusing on building modular micro-tissues with repeated functional units which facilitate a bottom-up approach.Here we report on the success and shortcomings of both top-down and bottom-up approaches to creating engineered corneal tissues. Specifically, we will discuss recent work demonstrating the importance of engineering corneal ECM with appropriate levels of tissue compliance using a top-down approach. We will then highlight a bottom-up approach, which focuses on fabricating discreet bio-prosthetic ECM building blocks (corneal lamellae) with specific micro-architectural features derived solely from human corneal keratocytes under serum free conditions using enzyme responsive templates. These building blocks will then be used to generate a whole cornea whilst maintaining the intricate architecture and complexity of native corneal ECM.