Douglas W. Chew

Differential Tensile Strength and Collagen Composition in Ascending Aortic Aneurysms by Aortic Valve Phenotype

BACKGROUND Ascending thoracic aortic aneurysm (ATAA) predisposes patients to aortic dissection and has been associated with diminished tensile strength and disruption of collagen. Ascending thoracic aortic aneurysms arising in patients with bicuspid aortic valve (BAV) develop earlier than in those with tricuspid aortic valves (TAV) and have a different risk of dissection. The purpose of this study was to compare aortic wall tensile strength between BAV and TAV ATAAs and determine whether the collagen content of the ATAA wall is associated with tensile strength and valve phenotype. METHODS Longitudinally and circumferentially oriented strips of ATAA tissue obtained during elective surgery were stretched to failure, and collagen content was estimated by hydroxyproline assay. Experimental stress-strain data were analyzed for failure strength and elastic mechanical variables: α, β, and maximal tangential stiffness. RESULTS The circumferential and longitudinal tensile strengths were higher for BAV ATAAs when compared with TAV ATAAs. The α and β were lower for BAV ATAAs when compared with TAV ATAAs. The maximal tangential stiffness was higher for circumferential when compared with longitudinal orientation in both BAV and TAV ATAAs. The amount of hydroxyproline was equivalent in BAV and TAV ATAA specimens. Although there was a moderate correlation between the collagen content and tensile strength for TAV, this correlation is not present in BAV. CONCLUSIONS The increased tensile strength and decreased values of α and β in BAV ATAAs despite uniform collagen content between groups indicate that microstructural changes in collagen contribute to BAV-associated aortopathy.

Effects of cyclic flexure on endothelial permeability and apoptosis in arterial segments perfused ex vivo.

Certain arteries (e.g., coronary, femoral, etc.) are exposed to cyclic flexure due to their tethering to surrounding tissue beds. It is believed that such stimuli result in a spatially variable biomechanical stress distribution, which has been implicated as a key modulator of remodeling associated with atherosclerotic lesion localization. In this study we utilized a combined ex vivo experimental/computational methodology to address the hypothesis that local variations in shear and mural stress associated with cyclic flexure influence the distribution of early markers of atherogenesis. Bilateral porcine femoral arteries were surgically harvested and perfused ex vivo under pulsatile arterial conditions. One of the paired vessels was exposed to cyclic flexure (0-0.7 cm(-1)) at 1 Hz for 12 h. During the last hour, the perfusate was supplemented with Evans blue dye-labeled albumin. A custom tissue processing protocol was used to determine the spatial distribution of endothelial permeability, apoptosis, and proliferation. Finite element and computational fluid dynamics techniques were used to determine the mural and shear stress distributions, respectively, for each perfused segment. Biological data obtained experimentally and mechanical stress data estimated computationally were combined in an experiment-specific manner using multiple linear regression analyses. Arterial segments exposed to cyclic flexure had significant increases in intimal and medial apoptosis (3.42+/-1.02 fold, p=0.029) with concomitant increases in permeability (1.14+/-0.04 fold, p=0.026). Regression analyses revealed specific mural stress measures including circumferential stress at systole, and longitudinal pulse stress were quantitatively correlated with the distribution of permeability and apoptosis. The results demonstrated that local variation in mechanical stress in arterial segments subjected to cyclic flexure indeed influence the extent and spatial distribution of the early atherogenic markers. In addition, the importance of including mural stresses in the investigation of vascular mechanopathobiology was highlighted. Specific example results were used to describe a potential mechanism by which systemic risk factors can lead to a heterogeneous disease.

Strain-Dependent Urethral Response

The Sprague–Dawley (SD) rat, an out‐bred, all‐purpose strain, has served well for lower urinary tract research. However, to test new cellular therapies for conditions such as stress urinary incontinence, an in‐bred rat strain with immune tolerance, such as the Lewis rat, may be more useful. The objective of this study was to reveal any differences in lower urinary tract continence mechanisms between the Lewis and SD rat.

Inhibition of Spleen Tyrosine Kinase for Rheumatoid Arthritis

Introduction: Spleen tyrosine kinase (Syk) is an important mediator of immunoreceptor signaling in macrophages, neutrophils, mast cells, and B cells. It is found on the synovium of rheumatoid arthritis (RA) patients, suggesting a role for Syk inhibition in the treatment of RA. In an earlier study, the Syk inhibitor R788 was administered for 12 weeks to a refractory RA population not responsive to methotrexate (MTX). Significant reductions in arthritis and serum levels of interleukin-6 were observed in those who received R788 as compared with placebo [1].

Cost-Effectiveness of Biologics Compared with Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis

Introduction: For many rheumatoid arthritis (RA) patients, RA leads to pain and stiffness, progressive joint destruction, functional disability, and premature mortality. The economic burden of RA is significant and includes direct costs (medical visits, medications, laboratory testing, and imaging) and indirect costs (lost productivity, early mortality, and out-ofpocket health care expenses). Disease-modifying antirheumatic drugs (DMARDs) slow the progression of joint damage and loss of function associated with RA. Newer but significantly more expensive biologic agents offer greater potential to slow disease progression and extend productivity, which raises the question of whether the improved clinical outcomes with biologics are worth their higher costs. Aims: This study identified and critically appraised existing economic evaluations of biologics versus DMARDs for adults with RA. Furthermore, it examined whether the incremental cost-effectiveness ratios (ICERs) were within the range of generally accepted medical interventions.

Association of Mechanical Properties and Collagen Content With Valve Morphology in Ascending Thoracic Aortic Aneurysmal Tissue

Bicuspid aortic valve (BAV) is the most common congenital heart malformation occurring in 1–2% of the population with a high rate of morbidity [1]. There is a significantly higher rate of dilation of the aortic root in adults with a BAV when compared to the normal population and this condition is often associated with ascending thoracic aortic aneurysm (ATAA). ATAA is characterized as an enlargement of the aorta to twice its normal diameter. If left untreated, ATAA can lead to aortic dissection or rupture. Therefore, ATAA is recommended for prophylactic surgery when its diameter reaches about 5.5 cm. However, in certain high-risk cases, such as patients with BAV, ATAA may rupture when its diameter is less than 5.5 cm. Since ATAA dissection and rupture are biomechanical phenomena, better mechanical models are needed to more accurately predict these events over the predictive capability of diameter alone.Copyright

3D Structural Information of Soft Tissues Using Small Angle Light Scattering

Small angle light scattering (SALS) is a extensively utilized technique for the rapid quantification of the organization and structure of native fibrous soft tissues. In the present work, we developed a method to extend serial histological sections to obtain 3D distribution architectural information. This technique allows for rapid quantification and study of general trends of architectural information over large volume or areas of tissue and is beneficial to study highly heterogeneous tissue where changes in architecture, due to pathologies or stress may induce complex regional changes. An important clinical example is learning the degree of organization of abdominal aortic aneurysm (AAA) tissue. When studying the organization trend in histological sections of AAA tissue, conclusions from the SALS 2D images cannot be drawn due to the high variability of organization from section to section. This is common to diseased tissues due to the altered structure that is otherwise organized in healthy tissue.Copyright

Characterization of Isolated Urethral Smooth Muscle Cells and Their Incorporation Into a Tissue Engineered Urethral Wrap

Millions of people worldwide suffer from an involuntary leakage of urine, a condition known as urinary incontinence. In the US alone, the estimated cost of managing this is more than

Mechanical and Chemical Stimulation of Bone-Marrow Stem Cells in a Three-Dimensional Fibrin Matrix: Preliminary Results

16 billion [1]. Stress urinary incontinence (SUI), the most common form, is characterized by involuntary leakage of urine from effort or exertion during actions such as laughing, coughing, or sneezing. SUI largely occurs as a result of weak or damaged pelvic muscles that support the bladder and urethra, which makes the urethra unable to maintain its seal and allows urine to leak. Current SUI treatments such as pelvic floor muscle training, vaginal inserts, pharmacologic therapeutics, and surgical procedures are limited by ineffectiveness and/or subsequent complications [2, 3].Copyright

The Effects of Culture Conditions and Implantation on the Structural and Mechanical Characteristics of a Tissue Engineered Urethral Wrap

The primary goal of tissue engineering is to develop a biological, mechanically-robust, and anti-thrombogenic vascular graft to replace diseased or damaged tissue and organs [1]. For example, researchers have incorporated smooth muscle cells (SMCs) into extracellular matrix to provide a living, functional conduits with the intended purpose of replacing SMC-containing tubes, such as the blood vessel, urethra, esophagus, intestine, etc. Although the preferred source is autologous cells to avoid immunological rejection, adult SMCs are difficult to obtain and expand. An alternative source of autologous cells could be bone marrow derived stem cells (BMSCs), which differentiate toward mesenchymal and hematopoietic lineages [2].Copyright