Martin A. Zulliger

Geometrical, functional, and histomorphometric adaptation of rat carotid artery in induced hypertension

Acute and long-term (up to 56 days) evolution of geometry, structural properties, vascular smooth muscle (VSM) tone and histomorphometric properties of the rat common carotid arteries under induced hypertension were investigated. Hypertension was induced in 8-week old male Wistar rats by total ligation of the aorta between the two kidneys. Rats were sacrificed 2, 4, 8 and 56 days postsurgery. The arterial wall layers thicken non-uniformly during the adaptation process, the inner layers thicken more in the acute phase of hypertension, whereas the outer layers of the wall are thicker than the inner layers at the end of the adaptation phase. Collagen content in the wall media exhibits a non-linear evolution, with a rapid increase in the acute hypertension phase followed by a slower increase at long-term. The elastin content increase is slight and steady, whereas VSM shows a steady but considerable increase which outdoes the collagen increase in long-term phase. VSM tone increases rapidly in the acute phase of remodelling (0-8 days) and this increase in tone contributes to a considerable increase in arterial compliance in the operating pressure range. At long-term (56 days) VSM tone returns to near control level, but compliance is even further increased, which suggests that at long-term the compliance increase is attributed primarily to structural remodelling.

Biomechanical adaptation of porcine carotid vascular smooth muscle to hypo and hypertension in vitro

Previous research in arterial remodeling in response to changes in blood pressure seldom included both hyper- and hypotension. To compare the effects of low and high pressure on arterial remodeling and vascular smooth muscle tone and performance, we have utilized an in vitro model. Porcine carotid arteries were cultured for 3 days at 30 and 170mmHg and compared to controls cultured at 100mmHg for 1 and 3 days. On the first and last day of culture, pressure-diameter and pressure-wall thickness curves were measured under normal smooth muscle tone using a high-resolution ultrasonic device. Last-day experiments included measurements where vascular smooth muscle was contracted or totally relaxed. From the data wall cross-sectional area, Hudetz elastic modulus and a contraction index related to the diameter reduction under normal smooth muscle tone were calculated. We found that although wall cross-sectional area (indicating wall mass) did not change much, Hudetz elastic modulus was significantly reduced in the 3-day hypotension group. Inspection of the wall contraction index suggests that this is due to a reduction in the vascular smooth muscle tone. Further, the peak of contraction index was found to be shifted to higher pressures in the 3-day 170mmHg group. We conclude that vascular smooth muscle performance adapts to both hypo- and hypertension at short time scales and can alter the biomechanics of the vascular wall in vitro.

Functional, mechanical and geometrical adaptation of the arterial wall of a non-axisymmetric artery in vitro

Objective Vascular remodeling is an adaptive response to variations in the hemodynamic environment acting on the arterial wall. Remodeling translates into changes of structure, geometry and mechanical properties of the artery. Our aim was to study the remodeling response of pig right common carotid arteries in vitro. Methods In vivo right carotid arteries are exposed to a non-uniform hemodynamic environment and exhibit a strong wall asymmetry in the circumferential direction that allows the study of two regions separately, as the artery remodels under in vitro perfusion. Porcine right common carotid arteries were cultured during 1 day (n = 6), 3 days (n = 6) or 8 days (n = 6) in an in vitro organ culture system, at a constant perfusion pressure of 100 mmHg. Geometrical, histological, biomechanical and biological analysis of the perfused segments was performed at the end of each study. Results Smooth muscle cell nuclei density and wall thickness remain constant along the culture periods. Elastin and collagen are significantly redistributed to equilibrate their relative content along the vessel circumference. The distensibility profile is significantly different at day 8. Matrix metalloproteinase-2 expression and activity increase significantly at days 3 and 8. Conclusion The non-axisymmetric arterial wall adapts to a uniform hemodynamic environment by redistributing the structural components of the extracellular matrix. The changes of collagen and elastin density may result from a vascular remodeling process involving matrix metalloproteinase-2 up-regulation and enzymatic activity. The remodeling response results in a new vascular wall configuration that is more distensible at physiological pressures (30–120 mmHg) and stiffer at higher pressures.

Three-Dimensional Quantitative Morphometric Analysis (QMA) for In Situ Joint and Tissue Assessment of Osteoarthritis in a Preclinical Rabbit Disease Model.

This work utilises advances in multi-tissue imaging, and incorporates new metrics which define in situ joint changes and individual tissue changes in osteoarthritis (OA). The aims are to (1) demonstrate a protocol for processing intact animal joints for microCT to visualise relevant joint, bone and cartilage structures for understanding OA in a preclinical rabbit model, and (2) introduce a comprehensive three-dimensional (3D) quantitative morphometric analysis (QMA), including an assessment of reproducibility. Sixteen rabbit joints with and without transection of the anterior cruciate ligament were scanned with microCT and contrast agents, and processed for histology. Semi-quantitative evaluation was performed on matching two-dimensional (2D) histology and microCT images. Subsequently, 3D QMA was performed; including measures of cartilage, subchondral cortical and epiphyseal bone, and novel tibio-femoral joint metrics. Reproducibility of the QMA was tested on seven additional joints. A significant correlation was observed in cartilage thickness from matching histology-microCT pairs. The lateral compartment of operated joints had larger joint space width, thicker femoral cartilage and reduced bone volume, while osteophytes could be detected quantitatively. Measures between the in situ tibia and femur indicated an altered loading scenario. High measurement reproducibility was observed for all new parameters; with ICC ranging from 0.754 to 0.998. In conclusion, this study provides a novel 3D QMA to quantify macro and micro tissue measures in the joint of a rabbit OA model. New metrics were established consisting of: an angle to quantitatively measure osteophytes (σ), an angle to indicate erosion between the lateral and medial femoral condyles (ρ), a vector defining altered angulation (λ, α, β, γ) and a twist angle (τ) measuring instability and tissue degeneration between the femur and tibia, a length measure of joint space width (JSW), and a slope and intercept (m, Χ) of joint contact to demonstrate altered loading with disease progression, as well as traditional bone and cartilage and histo-morphometry measures. We demonstrate correlation of microCT and histology, sensitive discrimination of OA change and robust reproducibility.

Implementation and application of a Monte Carlo model for an in vivo micro computed tomography system

Micro computed tomography (µCT) scanners are used to create high-resolution images and to quantify properties of the scanned objects. While modern µCT scanners benefit from the cone beam geometry, they are compromised by scatter radiation. This work aims to develop a Monte Carlo (MC) model of a µCT scanner in order to characterize the scatter radiation in the detector plane. The EGS++ framework with the MC code EGSnrc was used to simulate the particle transport through the main components of the XtremeCT (SCANCO Medical AG, Switzerland). The developed MC model was based on specific information of the manufacturer and was validated against measurements. The primary and the scatter radiation were analyzed and by implementing a dedicated tracing method, the scatter radiation was subdivided into different scatter components. The comparisons of measured and simulated transmission values for different absorber and filter combinations result in a mean difference of 0.2% ± 1.4%, with a maximal local difference of 3.4%. The reconstructed image of the phantom based on measurements agrees well with the image reconstructed using the MC model. The local contribution of scattered radiation is up to 10% of the total radiation in the detector plane and most of the scattered particles result from interactions in the scanned object. The MC simulations show that scatter radiation contains information about the structure of the object. In conclusion, a MC model for a µCT scanner was successfully validated and applied to analyze the characteristics of the scatter radiation for a µCT scanner.

Investigation on the resolution of a micro cone beam CT scanner scintillating detector using Monte Carlo methods

The impact of several physical quantities on the spatial resolution of an X-ray scintillating pixel detector for a micro cone beam CT (µCBCT) is investigated and discussed. The XtremeCT from SCANCO Medical AG was simulated using the EGSnrc/EGS++ Monte Carlo (MC) framework and extensively benchmarked in a previous work. The resolution of the detector was determined by simulating a titanium knife-edge to obtain the edge spread function (ESF) and the modulation transfer function (MTF). Propagation of the scintillation light through the scintillator and its coupling into the fiber optics system was taken into account. The contribution of particles scattered in the main scanner components to the detector signal is very low and does not affect the spatial resolution of the detector. The resolution obtained from the energy deposition in the scintillator without any blurring due to the propagation of the scintillation light into the fiber optics array was 31 µm. By assuming isotropic light propagation in the scintillator, the resolution degraded to 360 µm. A simple light propagation model taking into account the impact of the scintillators columnar microstructures was developed and compared with the MANTIS Monte Carlo simulation package. By reducing the width of the models light propagation kernel by a factor of 2 compared to the isotropic case, the detector resolution can be improved to 83 µm, which corresponds well to the measured resolution of 86 µm. The resolution of the detector is limited mainly by the propagation of the scintillation light through the scintillator layer. It offers the greatest potential to improve the resolution of the µCBCT imaging system.

WHOLE JOINT STRUCTURE IN A RAT OSTEOARTHRITIS MODEL FOR SAMPLE-SPECIFIC MECHANICAL EVALUATION

Micro-computed tomography (microCT) allows 3D assessment of calcified tissue structures in the joint, and recent advances involve the use of contrast agents to quantify glycosaminoglycan content in cartilage [Palmer 2006], alongside volume changes [Siebelt 2011]. However, challenges in clearly delineating the cartilage from the surrounding joint space still remain. Solving this would allow more accurate definitions of structural requirements for finite element (FE) studies of mechanical loading, which is an important determinant in the progression of osteoarthritis (OA). This work presents a method for clear delineation between cartilage, bone and joint space, for accurate structural definitions in future FE studies.