Tissue-Engineered Tracheal Replacement in a Child: A 4-Year Follow-Up Study.

In 2010, a tissue-engineered trachea was transplanted into a 10-year-old child using a decellularized deceased donor trachea repopulated with the recipient's respiratory epithelium and mesenchymal stromal cells. We report the child's clinical progress, tracheal epithelialization and costs over the 4 years. A chronology of events was derived from clinical notes and costs determined using reference costs per procedure. Serial tracheoscopy images, lung function tests and anti-HLA blood samples were compared. Epithelial morphology and T cell, Ki67 and cleaved caspase 3 activity were examined. Computational fluid dynamic simulations determined flow, velocity and airway pressure drops. After the first year following transplantation, the number of interventions fell and the child is currently clinically well and continues in education. Endoscopy demonstrated a complete mucosal lining at 15 months, despite retention of a stent. Histocytology indicates a differentiated respiratory layer and no abnormal immune activity. Computational fluid dynamic analysis demonstrated increased velocity and pressure drops around a distal tracheal narrowing. Cross-sectional area analysis showed restriction of growth within an area of in-stent stenosis. This report demonstrates the long-term viability of a decellularized tissue-engineered trachea within a child. Further research is needed to develop bioengineered pediatric tracheal replacements with lower morbidity, better biomechanics and lower costs.

Noradrenaline has opposing effects on the hydraulic conductance of arterial intima and media.

The uptake of circulating macromolecules by the arterial intima is thought to be a key step in atherogenesis. Such transport is dominantly advective, so elucidating the mechanisms of water transport is important. The relation between vasoactive agents and water transport in the arterial wall is incompletely understood. Here we applied our recently-developed combination of computational and experimental methods to investigate the effects of noradrenaline (NA) on hydraulic conductance of the wall (Lp), medial extracellular matrix volume fraction (ϕECM) and medial permeability (K11) in the rat abdominal aorta. Experimentally, we found that physiological NA concentrations were sufficient to induce SMC contraction and produced significant decreases in Lp and increases in ϕECM. Simulation results based on 3D confocal images of the extracellular volume showed a corresponding increase in K11, attributed to the opening of the ECM. Conversion of permeabilities to layer-specific resistances revealed that although the total wall resistance increased, medial resistance decreased, suggesting an increase in intimal resistance upon application of NA.

Computational fluid dynamics benchmark dataset of airflow in tracheas.

Computational Fluid Dynamics (CFD) is fast becoming a useful tool to aid clinicians in pre-surgical planning through the ability to provide information that could otherwise be extremely difficult if not impossible to obtain. However, in order to provide clinically relevant metrics, the accuracy of the computational method must be sufficiently high. There are many alternative methods employed in the process of performing CFD simulations within the airways, including different segmentation and meshing strategies, as well as alternative approaches to solving the Navier-Stokes equations. However, as in vivo validation of the simulated flow patterns within the airways is not possible, little exists in the way of validation of the various simulation techniques. The data presented here consists of very highly resolved flow data. The degree of resolution is compared to the highest necessary resolutions of the Kolmogorov length and time scales. Therefore this data is ideally suited to act as a benchmark case to which cheaper computational methods may be compared. A dataset and solution setup for one such more efficient method, large eddy simulation (LES), is also presented.

Intimal and medial contributions to the hydraulic resistance of the arterial wall at different pressures: a combined computational and experimental study.

The hydraulic resistances of the intima and media determine water flux and the advection of macromolecules into and across the arterial wall. Despite several experimental and computational studies, these transport processes and their dependence on transmural pressure remain incompletely understood. Here, we use a combination of experimental and computational methods to ascertain how the hydraulic permeability of the rat abdominal aorta depends on these two layers and how it is affected by structural rearrangement of the media under pressure. Ex vivo experiments determined the conductance of the whole wall, the thickness of the media and the geometry of medial smooth muscle cells (SMCs) and extracellular matrix (ECM). Numerical methods were used to compute water flux through the media. Intimal values were obtained by subtraction. A mechanism was identified that modulates pressure-induced changes in medial transport properties: compaction of the ECM leading to spatial reorganization of SMCs. This is summarized in an empirical constitutive law for permeability and volumetric strain. It led to the physiologically interesting observation that, as a consequence of the changes in medial microstructure, the relative contributions of the intima and media to the hydraulic resistance of the wall depend on the applied pressure; medial resistance dominated at pressures above approximately 93 mmHg in this vessel.

Power loss mechanisms in pathological tracheas.

The effort required to inhale a breath of air is a critically important measure in assessing airway function. Although the contribution of the trachea to the total flow resistance of the airways is generally modest, pathological alterations in tracheal geometry can have a significant negative effect. This study investigates the mechanisms of flow energy loss in a healthy trachea and in four geometries affected by retrosternal goitre which can cause significant distortions of tracheal geometry including constriction and deviation with abnormal curvature. By separating out the component of energy loss related to the wall shear (frictional loss), striking differences are found between the patterns of energy dissipation in the normal and pathological tracheas. Furthermore the ratio of frictional to total loss is dramatically reduced in the pathological geometries.

The effects of curvature and constriction on airflow and energy loss in pathological tracheas.

This paper considers factors that play a significant role in determining inspiratory pressure and energy losses in the human trachea. Previous characterisations of pathological geometry changes have focussed on relating airway constriction and subsequent pressure loss, however many pathologies that affect the trachea cause deviation, increased curvature, constriction or a combination of these. This study investigates the effects of these measures on tracheal flow mechanics, using the compressive goitre (a thyroid gland enlargement) as an example. Computational fluid dynamics simulations were performed in airways affected by goitres (with differing geometric consequences) and a normal geometry for comparison. Realistic airways, derived from medical images, were used because idealised geometries often oversimplify the complex anatomy of the larynx and its effects on the flow. Two mechanisms, distinct from stenosis, were found to strongly affect airflow energy dissipation in the pathological tracheas. The jet emanating from the glottis displayed different impingement and breakdown patterns in pathological geometries and increased loss was associated with curvature.

A combined numerical and experimental framework for determining permeability properties of the arterial media.

The medial layer of the arterial wall may play an important role in the regulation of water and solute transport across the wall. In particular, a high medial resistance to transport could cause accumulation of lipid-carrying molecules in the inner wall. In this study, the water transport properties of medial tissue were characterised in a numerical model, utilising experimentally obtained data for the medial microstructure and the relative permeability of different constituents. For the model, a new solver for flow in porous materials, based on a high-order splitting scheme, was implemented in the spectral/hp element library nektar++ and validated. The data were obtained by immersing excised aortic bifurcations in a solution of fluorescent protein tracer and subsequently imaging them with a confocal microscope. Cuboidal regions of interest were selected in which the microstructure and relative permeability of different structures were transformed to a computational mesh. Impermeable objects were treated fictitiously in the numerical scheme. On this cube, a pressure drop was applied in the three coordinate directions and the principal components of the permeability tensor were determined. The reconstructed images demonstrated the arrangement of elastic lamellae and interspersed smooth muscle cells in rat aortic media; the distribution and alignment of the smooth muscle cells varied spatially within the extracellular matrix. The numerical simulations highlighted that the heterogeneity of the medial structure is important in determining local water transport properties of the tissue, resulting in regional and directional variation of the permeability tensor. A major factor in this variation is the alignment and density of smooth muscle cells in the media, particularly adjacent to the adventitial layer.

Work dysfunction and addiction. Common roots.

A review of the literature identified similarities in the self-efficacy roots of substance abuse and vocational dysfunction, along with a potential benefit to providing vocational interventions as part of substance abuse treatment. Based upon the evidence presented, the author recommends the use of social cognitive counseling; using client functioning and level of care to guide vocational interventions; closely monitoring clients who are working; providing for ongoing social support; and committing to the availability of long-term aftercare and crisis intervention counseling to insure developmental gains are not lost.

A stable approach for coupling multidimensional cardiovascular and pulmonary networks based on a novel pressure-flow rate or pressure-only Neumann boundary condition formulation.

In many biomedical flow problems, reversed flows along with standard treatment of Neumann boundary conditions can cause instabilities. We have developed a method that resolves these instabilities in a consistent way while maintaining correct pressure and flow rate values. We also are able to remove the necessary prescription of both pressure and velocities/flow rates to problems where only pressure is known. In addition, the method is extended to coupled 3D/reduced-D fluid and fluid-structure interaction models. Numerical examples mainly focus on using Neumann boundary condition in cardiovascular and pulmonary systems, particularly, coupled with 3D-1D and 3D-0D models. Inflow pressure, traction, and impedance boundary conditions are first tested on idealized tubes for various Womersley numbers. Both pressure and flow rate are shown to match the analytical solutions for these examples. Our method is then tested on a coupled 1D-3D-1D artery example, demonstrating the power and simplicity of extending this method toward fluid-structure interaction. Finally, the proposed method is investigated for a coupled 3D-0D patient-specific full lung model during spontaneous breathing. All coupled 3D/reduced-D results show a perfect matching of pressure and flow rate between 3D and corresponding reduced-D boundaries. The methods are straight-forward to implement in contrast to using Lagrange multipliers as previously proposed in other studies.

Coupled and reduced dimensional modeling of respiratory mechanics during spontaneous breathing.

In this paper, we develop a total lung model based on a tree of 0D airway and acinar models for studying respiratory mechanics during spontaneous breathing. This model utilizes both computer tomography-based geometries and artificially generated lobe-filling airway trees to model the entire conducting region of the lung. Beyond the conducting airways, we develop an acinar model, which takes into account the alveolar tissue resistance, compliance, and the intrapleural pressure. With this methodology, we compare four different 0D models of airway mechanics and determine the best model based on a comparison with a 3D-0D coupled model of the conducting airways; this methodology is possible because the majority of airway resistance is confined to the lower generations, that is, the trachea and the first few bronchial generations. As an example application of the model, we simulate the flow and pressure dynamics under spontaneous breathing conditions, that is, at flow conditions driven purely by pleural space pressure. The results show good agreement, both qualitatively and quantitatively, with reported physiological values. One of the key advantages of this model is the ability to provide insight into lung ventilation in the peripheral regions. This is often crucial because this is where information, specifically for studying diseases and gas exchange, is needed. Thus, the model can be used as a tool for better understanding local peripheral lung mechanics without excluding the upper portions of the lung. This tool will be also useful for in vitro investigations of lung mechanics in both health and disease.

Endothelial nitric oxide synthase and calcium production in arterial geometries: an integrated fluid mechanics/cell model.

It is well known that atherosclerosis occurs at very specific locations throughout the human vasculature, such as arterial bifurcations and bends, all of which are subjected to low wall shear stress. A key player in the pathology of atherosclerosis is the endothelium, controlling the passage of material to and from the artery wall. Endothelial dysfunction refers to the condition where the normal regulation of processes by the endothelium is diminished. In this paper, the blood flow and transport of the low diffusion coefficient species adenosine triphosphate (ATP) are investigated in a variety of arterial geometries: a bifurcation with varying inner angle, and an artery bend. A mathematical model of endothelial calcium and endothelial nitric oxide synthase cellular dynamics is used to investigate spatial variations in the physiology of the endothelium. This model allows assessment of regions of the artery wall deficient in nitric oxide (NO). The models here aim to determine whether 3D flow fields are important in determining ATP concentration and endothelial function. For ATP transport, the effects of a coronary and carotid wave form on mass transport is investigated for low Womersley number. For the carotid, the Womersley number is then increased to determine whether this is an important factor. The results show that regions of low wall shear stress correspond with regions of impaired endothetial nitric oxide synthase signaling, therefore reduced availability of NO. However, experimental work is required to determine if this level is significant. The results also suggest that bifurcation angle is an important factor and acute angle bifurcations are more susceptible to disease than large angle bifurcations. It has been evidenced that complex 3D flow fields play an important role in determining signaling within endothelial cells. Furthermore, the distribution of ATP in blood is highly dependent on secondary flow features. The models here use ATP concentration simulated under steady conditions. This has been evidenced to reproduce essential features of time-averaged ATP concentration over a cardiac cycle for small Womersley numbers. However, when the Womersley number is increased, some differences are observed. Transient variations are overall insignificant, suggesting that spatial variation is more important than temporal. It has been determined that acute angle bifurcations are potentially more susceptible to atherogenesis and steady-state ATP transport reproduces essential features of time-averaged pulsatile transport for small Womersley number. Larger Womersley numbers appear to be an important factor in time-dependent mass transfer.

Psychotherapy with borderline patients: I. A comparison between treated and untreated cohorts.

OBJECTIVE: The aim of this study is to compare the clinical outcome of patients with borderline personality disorder (BPD) who had received outpatient psychotherapy for 1 year with BPD patients who received no formal psychotherapy for the same period. METHOD: Thirty patients with BPD were treated by trainee psychotherapists working according to clearly described therapeutic principles. They received intensive audiotaped supervision. Patients were seen twice weekly for 1 year. They were compared with 30 patients subsequently referred to the clinic, for whom no therapist was available and who remained on a waiting list for 1 year, receiving their usual treatment. The outcome measure was a score derived from DSM criteria. It was taken at the beginning and end of the year's treatment, in the former case, and after at least 1 year on the waiting list in the latter. (The average waiting period was 17.1 months.) RESULTS AND CONCLUSIONS: Patients who received psychotherapy were significantly improved in terms of the DSM score. Thirty percent of treated patients no longer fulfilled DSM-III criteria for BPD. The untreated patients were unchanged.