The number of individuals using electric powered wheelchairs (EPWs) is increasing every year. Advances in technology have led to the design of EPWs that are more complex and can perform multiple functions. The ANSI/RESNA wheelchair standards consist of a battery of tests that are designed to evaluate the safety and performance of both manual and power wheelchairs. However, there is a deficit of information available to the general public on the performance of wheelchairs on these tests. The purpose of this study was to compare the results of standards testing on five different types of EPWs. The value and intentions of each section of the standard were also reviewed and suggestions were made for possible improvements. A total of fifteen EPWs (three of each type) were tested using the following sections: static stability, dynamic stability, effectiveness of brakes, energy consumption, overall dimensions, speed and acceleration, seating dimensions, static, impact, and fatigue testing, climatic testing, obstacle climbing ability, and power and control systems. Statistical analysis was performed on the relevant sections. Significant differences were found between the different types of wheelchairs with respect to static stability, dynamic stability, braking distance, theoretical range, and obstacle climbing ability. The EPWs with the highest velocity and accelerations were found to be the most dynamically unstable and have the longest braking distances. Dynamic stability and braking distance were also found to be directly related to the slope of the test surface. It is apparent from the results that EPWs can differ in both performance characteristics and safety. Evaluation of the wheelchair standards also illustrated the need to continually revise the standards to keep pace with new technology. Stability, fatigue strength, and control system testing are three of the sections that will need to be adapted to help evaluate the next generation of EPWs.

ABSTRACT EFFECTS OF HORMONE REPLACEMENT THERAPY ON SYSTEMIC ARTERIAL PROPERTIES IN POST-MENOPAUSAL WOMEN Eric Alps Chen, B.S. University of Pittsburgh, 2002 Vascular stiffness properties contribute significantly to the arterial system hydraulic load. There is evidence that vascular stiffness plays a role in cardiovascular remodeling and may be an independent cardiovascular risk factor. Menopause accelerates age-associated increase in arterial stiffness and estrogen administration, which has vasodilating properties, can potentially mitigate this post-menopausal increase in stiffness. The present study examined the effects of chronic hormone replacement therapy (HRT) on systemic arterial mechanical properties in 35 post-menopausal women, divided into two groups: those receiving no HRT (Control, n = 25) and those receiving HRT (HRT-all, n = 10). The HRT-all group consisted of two subgroups: estrogen alone (HRT-E, n = 5) and a combination of estrogen and progesterone (HRT-EP, n = 5). Noninvasive data were collected serially at five times: once at the baseline during the first visit and during four subsequent visits after the initiation of the study at 19±1, 108±5, 193±4, and 388±8 days, respectively. Heart rate (HR), stroke volume (SV), and cardiac output (CO) did not change significantly in the control group throughout the study. This was also true for both HRT groups, except for a small decrease in HR at Visits 3 and 4 for the HRT-E group and an increase in CO at Visit 3 in the HRT-EP group. Mean arterial pressure decreased over time in control and both HRT groups, reaching statistical significance at later times (fifth visit). Systemic vascular resistance did not change significantly in control and both HRT groups. Global arterial compliance (AC) was unchanged for the control group but tended to increase in the HRT-all group, although no statistical significance was reached. In contrast, the subgroup analysis revealed that AC increased for the HRT-E subgroup, reaching statistical significance at the fifth visit. Similarly, significant decrements in pulse wave velocity (PWV), an index of regional vascular stiffness, were observed only for the HRT-E group. In conclusion, AC increased (vascular stiffness decreased) in subjects receiving chronic estrogen therapy only. The inclusion of progesterone seems to counteract the estrogen-mediated decrease in vascular stiffness, indicating that the vascular stiffness-associated cardio-protective effects of HRT, if any, may be limited to estrogen administration alone.

Platelet-mediated thrombosis is a significant source of morbidity and mortality in cardiovascular device patients. Although Virchow elucidated the mechanisms governing thrombus formation over 100 years ago, the underlying processes have proven difficult to describe mathematically. A reliable, predictive thrombosis model would be a valuable aid to designers of artificial organs. A comprehensive model of platelet-mediated thrombogenesis should simulate red-cell-enhanced platelet transport, platelet activation, kinetics and mechanics of platelet deposition and aggregation, flow disturbances due to thrombus growth, thrombus disruption by fluid forces, and interactions between platelets and the coagulation cascades. Most models focus on these components individually; a unified approach is lacking. The contribution of this thesis is a computational model of platelet thrombosis which incorporates many, though not all, of these essential components. This two-dimensional continuum model, based on prior work, is comprised of seven coupled species conservation equations, which model shear-enhanced platelet transport, platelet-platelet and platelet-surface adhesion, agonist-induced platelet activation, platelet-phospholipid-dependent thrombin generation, and heparin-catalyzed thrombin inhibition. The model is first validated for Poiseuille flow of whole human blood over collagen. Very good agreement between predicted and experimentally measured platelet deposition is obtained for wall shear rates ranging from 100 to 1000/s. At 1500/s, however, the model fails to predict the shape of the experimental curve. This may be due to the higher shear rate, or to unmodeled effects of the chelating agent used as the anticoagulant in this study. Next, two-dimensional flow over collagen is considered. For a tubular expansion with no agonists, good agreement with experiments can be obtained in the recirculation zone, but deposition in the fully-developed downstream region is greatly under-predicted. Surprisingly, deviation from experiments is worse at 0% than at 20% hematocrit. Similarly, for an axisymmetric stenosis with agonists present, the model does most poorly at predicting deposition in the downstream regions. These discrepancies are attributed to the approximation of blood as a single continuum, rather than as a suspension. In a preliminary step toward correcting these deficiencies, an attempt is made to use existing two-phase flow models to predict platelet and red blood cell concentrations in fully-developed tube flow.

Gradient-oriented boundary profiles have been developed as a novel method to parameterize boundaries. Boundary profiles are created at locations of high gradient magnitude by averaging intensity within a neighborhood of voxels oriented along the image gradient, making them rotationally invariant and relatively insensitive to image noise. A cumulative Gaussian is fit to the collection of averaged voxel intensities yielding estimates of (1) extrapolated intensity values for voxels located far inside and outside of a boundary and (2) anatomical boundary location. Intrinsic measures of confidence have been developed to eliminate low-confidence parameter estimates. Thresholds placed on these measures of confidence allow for high-confidence unsupervised classification of boundaries. The validity of gradient-oriented profiles is demonstrated on artificially generated three-dimensional test data and shown to accurately parameterize and classify the boundary. Applying the measures of confidence and establishing thresholds, the accuracy of boundary location and intensities estimates improved drastically, making them a high-quality replacement for simpler methods of boundary detection. Towards shape analysis, gradient-oriented boundary profiles are applied to an existing a medial-based approach to shape analysis, known as core atoms. Core atoms in their previous implementation were based on simple gradient direction and unable to form without a priori knowledge of object intensity relative to background. Boundary profiles were applied to core atoms permitting the formation of so called core profiles. Core profiles remove any restriction on the objects or the backgrounds intensity, allowing multiple objects of differing intensities to be located with a single application. Core profiles were applied to 3D computer-generated data, as well as RT3D ultrasound cardiac phantom data. It was shown on computer-generated data that calculating the volume with core profiles is more accurate then calculating the volume with core atoms, because of the improved accuracy of the boundary location. Two new methods of automatically measuring volume on non-parametric data with core profiles are proposed. Future work with includes constructing medial node models improved by gradient-oriented boundary profiles for automated left ventricular identification and measurement.

Diabetes Mellitus is one of the predominant contributors to morbidity and mortality worldwide. Prior to the advent of insulin therapy, patients suffering from Type I diabetes generally did not survive past childhood. Even with insulin therapy, a physiologically normal insulin response to increased systemic glucose cannot be achieved. Pancreatic islet transplantation has been shown to restore the physiological response to glucose, but risks associated with chronic immune suppression outweigh the benefit of tighter glucose regulation. This study investigates the potential of covalent modification of pancreatic islets with poly(ethylene glycol) (PEG) to abrogate the immune response towards transplanted islets and eliminate the need for chronic immune suppression. Previous studies have shown that PEG can be covalently bound to islet extracellular matrix (ECM) and surface proteins with no adverse affect on islet viability or function. The goal of this study was to determine the effect of covalent PEG modification on binding of islet-specific antibody, and to determine whether or not PEG modification could prolong graft survival in vivo. By a novel adaptation of an enzyme-linked immunosorbent assay (ELISA) the amount of islet-specific antibody bound to unmodified or PEG-modified islets was compared semi-quantitatively. Islets treated with 40kD branched PEG-NHS bound significantly more antibody than untreated controls. Based on the students paired t-test there was no statistically significant change in antibody binding between 5kD PEG-treated and unmodified islets, although 7 of 9 PEG treated groups in this experiment bound less antibody than the corresponding unmodified groups. For in vivo islet transplantation , there was no difference in graft survival observed between PEG-treated and untreated grafts. Although PEG treatment did not have an apparent effect on in vivo graft survival, the effects observed in the antibody binding experiment suggest that PEG does modify antibody binding and further investigation of this technique is warranted.

Endothelial dysfunction is characterized by the upregulation of leukocyte adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), and has been identified in numerous disease processes including inflammation, atherosclerosis, transplant rejection, and neoplasia, yet current clinical techniques to assess endothelial dysfunction are limited. An ultrasound-based molecular imaging technique to detect cell surface markers of endothelial dysfunction may offer non-invasive assessment of associated disease processes. Lipid-based ultrasound contrast microbubbles were targeted to ICAM-1 by conjugation with anti-ICAM-1 antibodies. These targeted microbubbles should selectively adhere to dysfunctional endothelium overexpressing ICAM-1, producing stronger and more persistent contrast enhancement during ultrasound imaging. Previous results from our laboratory demonstrated that ICAM-1-targeted microbubbles preferentially adhere to inflammatory versus normal endothelium in vitro under static conditions. In the current studies, we first verified that ICAM-1 was upregulated in a variety of inflammatory models using immunohistochemistry. Next, various parameters that modulate adhesion of targeted microbubbles to dysfunctional endothelium were investigated. We quantified and demonstrated control over the final antibody density on the microbubble. Using a parallel plate perfusion chamber and a radial flow chamber, ICAM-1-targeted microbubble adhesion to cultured human endothelium was shown to be greater to inflammatory than non-inflammatory cells, and linearly dependent on microbubble antibody density, wall shear rate, and endothelial ICAM-1 density. In vivo experiments using a rat heart transplant model demonstrated that ultrasound imaging using ICAM-1-targeted microbubbles can non-invasively detect acute cardiac allograft rejection. Using a mouse subcutaneous tumor model, we demonstrated that ultrasound imaging using microbubbles targeted via a tumor endothelium-specific binding peptide can non-invasively identify tumor vasculature. These data have implications for the development of targeted contrast agents capable of identifying endothelial molecular markers of disease, and offer promise for the optimization and clinical application of a targeted, contrast-enhanced ultrasound imaging technique for the diagnosis and monitoring of disease states associated with endothelial dysfunction.

It is estimated that there are 85,000 serious wheelchair accidents annually, of which 80% are attributable to tips and falls. Despite the increasing trend in wheelchair accidents every year, there is little literature on the cause and prevention of these accidents. Test dummies provide an ethical and practical alternative to subjects when assessing the risks and prevention mechanisms of tips and falls in controlled studies. However, design criteria for anthropomorphic test devices (ATDs) were based on the response and tolerance data acquired from cadaver studies and human volunteers. Such cadavers are typically of advanced age, and have anthropometrics reflecting a healthy, unimpaired population. For that reason, use of ATDs in relatively low speed wheelchair studies may under estimate the risk of injury. The purpose of this study was to develop and validate a low speed, low impact test dummy for use in the study of the prevention of tips and falls from wheelchairs. A kinematic analysis comparing the trunk bending of a Hybrid III test dummy (HTD) to that of a wheelchair user during various braking trials served for validation. In addition, a dynamic model was used to determine underlying causes of the motion. Statistical differences were not found (p>.05) in the peak trunk angular range of motion, velocity, and acceleration measures of a modified HTD over a range of wheelchair speeds and decelerations. This is promising evidence that the test dummy is a suitable surrogate for a wheelchair user in low speed dynamic studies. However, the HTD underestimated the motion of a wheelchair test pilot during the fast speed and power-off braking condition. A dynamic model consisting of a cart with an inverted pendulum was used to provide additional insight into the differences in motion. Although the model produced consistent values for damping and stiffness coefficients, evidence indicates that the functional form of the model may be incorrect. The model likely estimated properties for a wheelchair/rider system rather than only the rider. Further analysis showed an impingement occurring between the pelvis and thighs of the HTD. Removing the impingement will further increase the similarities between the HTD and test pilot.

The urinary bladder stores urine and permits proper micturition, both functions that are inherently mechanical. Bladder research to date has been limited to whole-organ testing and simple uniaxial study, both of which are inadequate for comprehensive modeling and rigorous analysis of the mechanical properties of the bladder wall. In this work, we studied the quasi-static and time-dependent properties of the bladder wall to further understand bladder function. To obtain the requisite multiaxial data we utilized biaxial testing techniques, which allow for a more realistic physiological loading state. The goal of the study was to develop a comprehensive understanding of bladder wall biomechanics to provide insight into tissue-level bladder function. This information can be compared against other ongoing and future studies of pathologies to aid in the design of clinical treatments. The results indicated that bladder tissue 10 days after spinal cord injury was more compliant than normal bladder when referenced to the preconditioned state. However, the preconditioned state itself was different between normal and spinal-cord-injured groups, indicating large rapid changes in structure. There was a fundamental change in material behavior after spinal cord injury that indicates structural rearrangement on a microstructural fiber level. Unlike other soft tissues, there was no difference in mechanical response over three orders of magnitude of loading strain rate, most likely due to the large range of bladder function, including fast emptying and very slow filling. The time-dependent stress relaxation tests indicated that bladder behavior was dependent on stress level, with less relaxation occurring at higher stress levels. This may be because the massive structural rearrangements during normal function cause more collagen to bear load at higher stress levels as protection from over distention. This study provided the first mechanically rigorous information regarding the tissue properties of the normal bladder wall, including comparisons to a diseased state. This information can be used to understand how differences in structure caused by disease alter the tissue behavior, and hence the biological function, of the urinary bladder.

Therapeutic antibody removal is performed to facilitate ABO-incompatible kidney transplants and heart and kidney xenotransplants, and to treat Goodpasture syndrome, myasthenia gravis, hemophilia with inhibitors, and thrombocytopenic purpura. Antibody removal is achieved non-selectively, via plasma exchange, or semi-selectively, via plasma perfusion through immunoadsorption columns containing immobilized protein A. We are developing hollow fiber-based specific antibody filters (SAFs) that selectively remove antibodies of a given specificity directly from whole blood, without separation of the plasma and cellular blood components and with minimal removal of plasma proteins other than the targeted antibodies. The working unit of the SAF is a hollow fiber dialysis membrane with antigens, specific for targeted antibodies, immobilized on the inner fiber wall. Several thousand SAF fibers are connected in parallel to produce a filter similar in construction to a hollow fiber hemodialyzer. A principal goal of our research is to identify the primary mechanisms that control antibody transport within the SAF, and to use this information to guide the choice of design and operational parameters that maximize the SAF-based antibody removal rate. We approached this goal by formulating a simple mathematical model of SAF-based antibody removal and performing in vitro antibody removal experiments to test key predictions of the model. Our model revealed three antibody transport regimes, defined by the magnitude of the Damköhler number Da (antibody-binding rate/antibody diffusion rate): reaction-limited (Da ≤ 0.1), intermediate (0.1 < Da < 10), and diffusion-limited (Da ≥ 10). For a given SAF geometry, blood flow rate, and antibody diffusivity, the highest antibody removal rate was predicted for diffusion-limited antibody transport. We performed in vitro antibody removal experiments in which SAFs containing immobilized bovine albumin (BSA) were used to remove anti-BSA antibodies from buffer. The measured anti-BSA removal rates were consistent with antibody transport in the intermediate regime. We concluded that initial SAF development work should focus on achieving diffusion-limited antibody transport by maximizing the SAF antibody-binding capacity. If diffusion-limited antibody transport is achieved, the antibody removal rate can be raised further by increasing the number and length of the SAF fibers and by increasing the blood flow rate through the SAF.

The effects of valve leaflet mechanical properties on the dynamic geometry and function of the aortic heart valve are, to date, not well understood. This is largely due to the complex anatomy and solid-fluid interactions inherent in valve function. In the present study, the effects of leaflet stiffness on the dynamic aortic valve leaflet 3D geometry were quantified using a novel, non-contacting imaging system over the complete cardiac cycle. The imaging system utilized a structured laser-light imaging method, incorporated into a physiological flow loop, to project a high density matrix of laser dots onto the leaflet surface. The resulting dot pattern defined the leaflet surface, and was imaged by a pair of borescopes equipped CCD cameras providing stereographic views. From the image pairs, 3D dot coordinates were recovered using the direct linear transformation method. Five native porcine aortic heart valves were imaged, and then mechanically stiffened using a 0.625% aqueous glutaraldehyde fixation for 24 hours while under 4 mmHg transvalvular pressure. The valve was then re-imaged under near-identical flow conditions. Area, dimensional, surface curvature, and measurements were performed. We observed that: 1) the native valve elongates in the radial direction by ~30% when fully opened, and exhibited small, high frequency shifts in shape; 2) the stiffened leaflet demonstrated a more stabile shape, as well as focal regions of prolonged, high curvature; 3) the stiffened leaflet opens and closes faster by ~10 ms compared to native leaflet; 4) for both native and stiffened states, the aortic valve opened from basal region leading to free edge 5) when closing, both the native and stiffened state valve close with both free edge and circumferential together. Clearly, valve leaflet undergo complex geometric changes during the cardiac cycle, and leaflet mechanical properties (mainly stiffness) have a profound affect on leaflet dynamic geometry. Overall, the primary findings of this study were the extensive radial distension in the native state, and that an increase in leaflet mechanical stiffness induces high bending areas. The physiological function and advantage of the radial distension is currently unknown, but may affect the local hemodynamic patterns during valve operations, especially in the sinus regions. Our findings for the stiffened tissue have implications to valve design. For example, the high bending observed in the stiffened state correlated with known locations of tissue deterioration previously reported in our laboratory. Thus, in order to minimize leaflet tissue damage, methods of chemical modification utilized in bioprosthetic heart valves that maintain leaflet flexibility are necessary to minimize the onset and progression of tissue damage.