With recent advances in workstation technology, operators are often asked to perform complex tasks that require a tremendous amount of real-time information processing. In order to avoid poor task performance due to the operators cognitive limitations, it would be advantageous to be able to probe an operators cognitive state while performing such tasks. The current study investigates whether operators exhibit changes in seated posture as a result of changing cognitive task conditions. Furthermore, the current study presents means of quantifying such seated postural changes in real-time and uses these measures to construct an implicit cognitive state gauge. Fourteen subjects performed a simulated airspace monitoring task in which they tracked multiple 75.0 sec long waves of incoming aircraft with various levels of difficulty. Subjects were instructed to identify all incoming aircraft and to attend to them based on the level of threat that they posed. While performing the task, subjects seated postural changes were monitored by tracking the distribution of pressure over the seat and back pads of the chair. This distribution of pressure was used to calculate changes in seated center of pressure, seat torsion, and the extent to which subjects used the back of the chair to brace themselves. Subjects demonstrated a significant decrease in seated postural changes over the course of more difficult waves (high number of aircraft on screen) in comparison to easier waves (low number of aircraft on screen). When subjects completed waves with 24 tracks on screen compared to waves with 6 tracks on screen, the distance traveled by the seated center of pressure decreased 40.3%, transverse-plane seat torsion decreased 32.2%, and the total change in distance between the left and right ischial tuberosities decreased 38.1% on average. The extent to which subjects postural changes were correlated to the changing number of tracks on screen was consistently high while the number of tracks on screen was increasing and was consistently low after the maximum number of tracks on screen had been presented. It was concluded that monitoring seated posture is effective for gauging how subjects update their awareness of task conditions in real-time.

Scaffolds composed of extracellular matrix (ECM) and derived from various species and various organs have been shown to promote constructive, site-specific tissue remodeling in pre-clinical studies and clinical use, including musculoskeletal, urogenital, dermal, cardiovascular, and neural applications. Despite extensive study, the mechanisms of the remodeling process are still not thoroughly understood. The goals of this dissertation were to elucidate the role of mechanical loading in the remodeling of ECM scaffolds and the role of bone marrow derived cells in the remodeling process. To better understand the role of mechanical loading on the remodeling of an ECM scaffold, an ECM scaffold derived from the porcine small intestinal submucosa (SIS-ECM) was seeded with fibroblasts and subjected to a variety of magnitudes and frequencies of cyclic strain using a custom designed Cyclic Stretching Tissue Culture system. The magnitudes of stretch were based on a study of the collagen fiber kinematics of the SIS-ECM under uniaxial and biaxial loading conditions. The cyclic loading experiments showed that mechanical loading led to expression of matrix related genes that was consistent with a constructive remodeling response with increased expression of collagen type I (Col I), á-smooth muscle actin (SMA), and tenascin-C (TN-C), as well as decreased expression of collagen type III (Col III). It was also found that bone marrow cells were recruited to the site of ECM remodeling and that the cells remained at the site of remodeling for 16 weeks after implantation, unlike an autologous tendon repair. Furthermore, it was found that the bone marrow derived cells did not express the hematopoietic marker CD45, but did express Col I, Col III, and SMA. The cells did not show the same expression pattern as normal tendon fibroblast (Col I+, TN-C+), suggesting that the cells differentiated towards a myofibroblastic cell as opposed to a normal fibroblast. The results of this study show that an ECM scaffold recruits a bone marrow derived mesenchymal progenitor to the site of remodeling, and that those cells differentiate into site specific tissue as a result of mechanical and biochemical cues.

Transcranial electrical stimulation (TES) appears to be an effective way to monitor the spinal cord while patients are under anesthesia. This method is sensitive to changes in the functioning of the corticospinal tracts. It is a reliable and fast indicator of the status of the spinal cord during surgery. In this research, we develop a model to describe the intracranial voltage, electric field, and activation function distributions associated with transcranial electrical stimulation. Poissons equation is utilized with boundary conditions modeled after a real human head. The models, which are a two dimensional (2D) circular volume conductor and a three dimensional (3D) spherical volume conductor, include the inhomogeneous aspects of a human head. These inhomogeneous characteristics impact the flow of current due to volume conductivity differences between the scalp, skull, cerebrospinal fluid, and the brain itself. These results for a theoretical head model show the systematic differences between 2D and 3D models which has not been examined for TES. Knowing the differences between 2D and 3D simulations allows the inference for the results of the 3D case using a 2D model, which saves time and computational resources. A comparison of the voltages, electric fields, and activation functions is examined to determine the differences between the 2D and 3D models for each quantity. Parameterizations are also performed to show the impact of the different layers of the head. The results from the potentials, electric fields, activation function and parameterization calculations are used to infer the systematic differences between 2D and 3D models. This analysis of computational models for TES has not been performed before and is beneficial to diagnosing which areas of the brain are being stimulated during TES and gives an idea of the stimulation threshold needed to achieve muscle responses via TES.

Chronic recordings from micromachined neural electrode arrays often fail a few weeks after implantation primarily due to the formation of an astro-glial sheath around the implant. We propose a drug delivery system, from conducting polymer (CP) coatings on the electrode sites, to modulate the inflammatory implant-host tissue reaction. In this study, polypyrrole (PPy) based coatings for electrically controlled and local delivery of the ionic form of an anti-inflammatory drug, dexamethasone (Dex), was investigated. The drug was incorporated in PPy via electropolymerization of pyrrole and released in PBS using cyclic voltammetry (CV). FTIR analysis of the surface showed the presence of Dex and polypyrrole on the coated electrode. The thickness of the coated film was estimated to be ~50 nm by ellipsometry. We were able to release 0.5 µg/cm2 Dex in 1 CV cycle and upto 92% Dex after 30 CV cycles. In-vitro studies and immunocytochemistry on murine glial cells suggest that the released drug lowers the count of reactive astrocytes to the same extent as the added drug. In addition, the released drug is not toxic to neurons as seen by healthy neuronal viability in the released drug treated cells.

This thesis concentrates on the reduction of field (both main field B0 and RF field B1) inhomogeneity in MRI, especially at high B0 field. B0 and B1 field inhomogeneity are major hindrances in high B0 field MRI applications. B1 inhomogeneity will lead to spatially varying signal intensity in the MR images. B0 inhomogeneity produces blurring, distortion and signal loss at tissue interfaces. B0 artifacts are usually termed off-resonance or susceptibility artifacts. None of the existing methods can perfectly correct these inhomogeneity artifacts. This thesis aims at developing three-dimensional (3D) tailored RF (TRF) pulses to mitigate these artifacts. A current limitation in the use of 3D TRF techniques, however, is that pulses are often too long for practical clinical applications. Multiple transmission techniques are proposed to decrease pulse lengths and provide an inherent correction for B1 inhomogeneity. Shorter pulses are also more robust to profile distortions from susceptibility effects. Specifically, slice-selective 3D TRF pulses for multiple (or ¡°parallel¡±) transmitters were designed and validated in uniform phantom and human brain experiments at 3 Tesla. A pseudo-transmit sensitivity encoding (¡°transmit SENSE¡±) method was introduced using a body coil transmitter and multiple receivers to mimic the real parallel transmitter experiment. The kz-direction was controlled by fast switching of gradients in a fashion similar to Echo planar imaging (EPI). The transverse plane (kx-ky) was sampled sparsely with hexagonal trajectories, and accelerated with the transmit SENSE method. The transmit SENSE 3D TRF pulses reduced the B1 inhomogeneity compared to standard SINC pulses in human brain scans. The undersampled transmit SENSE pulses were only 4.3ms long and could excite a 5mm thick slice, which is very promising for clinical applications. Furthermore, these pulses are shown by numerical simulation to have promise in correcting through-plane susceptibility artifacts.

In cases of craniosynostosis, defined as the premature fusion of the cranial sutures, there is a need to inhibit bone formation in small calvarial defects to avoid the occurrence of postoperative resynostosis. Similarly, reconstruction of bone in the craniofacial skeleton following injury or tumor resection necessitates controlled bone regeneration to avoid bone overgrowth. Bone morphogenetic proteins (BMPs) are potent bone inducing growth factors that are expressed during normal bone healing. Noggin is an extracellular antagonist to BMPs. This work studied the use of Noggin to prevent postoperative resynostosis in a rabbit model of human nonsyndromic craniosynostosis via protein therapy. A mouse model of a healing suturectomy was also developed. This model was used to study the effects of Noggin ex vivo gene therapy on the inhibition of postoperative resynostosis. Finally, the ability of Noggin to inhibit bone overgrowth and improve BMP4-induced bone formation was tested. The work presented here demonstrates that a single dose of Noggin protein is capable of inhibiting resynostosis and improving craniofacial growth after surgery to correct craniosynostosis in rabbits. Noggin delivered through ex vivo gene therapy was able to inhibit bone formation in a novel mouse model. Also, the implantation of Noggin expressing cells along with BMP4 expressing cells reduced ectopic bone formation and improved bone density. These results suggest that Noggin therapy may be useful for the inhibition of postoperative resynostosis in children with craniosynostosis. Furthermore, by recreating naturally occurring expression patterns (for example, both Noggin and BMP4), we may be able to control the size, shape and quality of bone formed by biologically-driven therapies.

A dynamic balloon volume sensor system (DBVSS) was designed for use with the intra-aortic balloon pump (IABP), a therapeutic device to assist heart recovery after cardiac dysfunction or cardiac trauma, and the Pittsburgh respiratory support catheter (RSC), an internally deployed gas exchange device which augments lung function. The DBVSS was designed to detect the degree of inflation of the balloons incorporated into each device as they pulse within a patient. Both devices require full inflation for optimal performance, and both will under-inflate during normal operation. The sensor system requirements were to measure volumes within 10% of the actual across the range of expected pulsation frequencies as well as in changing concentrations of helium. The DBVSS employed a hot wire anemometer to detect the flow entering the balloon, combined with a computer algorithm to integrate the flow to find volume. The system compensated for the flow reading changes resulting from changing helium concentration by measuring gas properties during zero gas flow between pulsations, and used this data to correct the flow profile at each helium concentration. The volume from the DBVSS was compared to the volume standard as measured by water displacement in a plethysmograph. The system was able to accurately measure delivered balloon volume under changing gas composition as well as detected volume loss from the balloon across helium concentrations. The DBVSS measured the volume within 10% across these tests, as well as under compression of the balloon, high resistance in the driveline and across frequencies up to 480 beats per minute. The DBVSS was proved to be within the design requirements for helium concentration and inflation methods for both the devices considered.

A classification procedure was developed that uses hidden Markov models (HMMs) to identify sub-groups within a chronic lower back pain (CLBP) patient population based on their time series of lifting patterns during a repetitive lifting task. Based on clinical observations of a repetitive lifting task, our approach assumed that the patient population was composed of two groups: one group that performed lifts more similar to controls than to other patients and another group that lifted differently from control subjects. Two HMMs were designed to describe the repetitive lifting data, one derived from the control subject data and one derived from the CLBP subject data. The HMMs were designed based on the results of a data reduction procedure that reduced and combined the multidimensional lifting parameters into discrete lifting patterns using factor analysis and cluster analysis. Simulation studies were performed to demonstrate that the HMMs could reliably identify subjects from one group that were intentionally mislabeled as the other group. When the HMMs were applied to clinical data, 35 of the 81 CLBP subjects were classified to the control HMM and 46 were classified to the CLBP HMM. For the control group, 46 of 53 control subjects were classified to the control HMM and only seven were classified to the CLBP HMM. The CLBP groups were found to use different lifting patterns during the task. The CLBP subjects that were classified to the CLBP HMM were found to use a lifting pattern that involves slow, controlled movements. Self-reported measures of the two groups of CLBP subjects were compared and self-reported pain intensity, pain severity and perceived self-efficacy found to be statistically different. The CLBP subjects that were classified to the CLBP HMM reported higher pain intensity and pain severity, and lower self-efficacy suggesting that the CLBP population is heterogeneous and that the HMM classification procedure can successfully identify two meaningfully different sub-groups of CLBP patients.

The prevalence of bone and articular cartilage injuries is expected to increase with the aging population. As a possible therapeutic option, stem cell-based therapies are being investigated. It has previously been reported that muscle-derived stem cells (MDSCs) isolated from mouse skeletal muscle can undergo osteogenic and chondrogenic differentiation in vitro and in vivo when stimulated with bone morphogenetic protein 4 (BMP4). One goal of this project was to determine whether cell sex influences this differentiation potential. Using in vitro osteogenic assays, it was determined that male MDSCs (M-MDSCs) stimulated with BMP4 expressed osteogenic markers and displayed more mineralization than female MDSCs (F-MDSCs). In vivo, M-MDSCs expressing BMP4 and implanted into the hind limb of mice induced a more robust ectopic bone formation when compared to F-MDSCs. These results suggest that cell sex influences the osteogenic differentiation potential of MDSCs. In the second study, the signaling pathways involved during BMP4 stimulation were investigated to further characterize the osteogenic differentiation process. The phosphatidyl inositol 3-kinase and p38 MAPK pathways played a positive role in MDSC osteogenesis, while the extracellular signal-regulated kinase pathway was identified as a negative regulator of osteogenesis. These results suggest that the osteogenic differentiation of MDSCs could be manipulated by regulating these pathways. In the third study, the effect of BMP4 and transforming growth factor-b1 (TGF-b1) on the chondrogenic differentiation of F- and M-MDSCs in vitro was investigated. All MDSCs tested underwent chondrogenic differentiation, with no significant sex-related differences observed. However, addition of TGF-b1 synergistically enhanced BMP4-induced chondrogenic differentiation. In the final study, the effect of mechanical stimulation on the proliferation and osteogenic differentiation of MDSCs was investigated by using both biaxial and uniaxial strain. Mechanical stimulation affected cell orientation, but did not significantly affect the proliferation or osteogenic differentiation of MDSCs. In conclusion, the BMP4-induced osteogenic and chondrogenic differentiation of MDSCs can be influenced by several factors including cell sex and growth factors and can be guided through the manipulation of cell signaling pathways. The results from this project support the continued investigation of MDSCs as a potential cell source for bone and articular cartilage tissue engineering.

Shoulder arthroplasty, the most common treatment option for patients diagnosed with end-stage glenohumeral osteoarthritis, is able to provide pain relief and restore some functionality. However, this highly advanced surgical procedure often suffers from a major complication of glenoid prosthesis loosening. The problem is magnified during repeat surgeries mainly due to the minimal quantity of bone in the glenoid vault. The goals of this dissertation were to perform structural analysis of normal and osteoarthritic glenoid, evaluate glenoid design variable effects on restoring long-lasting functionality to damaged shoulders, and create a finite element model (FEM)-based simulation process for computing subject-specific internal glenoid bone remodeling. 3D computer models of normal and osteoarthritic scapulae were created using high-resolution volumetric computed tomography images. The computer models were used for glenoid structural analyses. The morphological measurements were comparable to prior studies. The glenoid was found to be approximated by geometric analogs. The osteoarthritic scapula was highly retroverted compared to the normal, and had relatively higher glenoid bone density. Internal glenoid morphology was quantified for the first time. Two and three dimensional stress analysis was used to compare glenoid prosthesis design variables. A custom program assigned location-specific material properties to the bone elements, based on the computed tomography data, making the FEMs similar to the actual scapula. Cemented or uncemeneted polyethylene pegs, compared to metal, gave stresses comparable to intact scapula. Two dimensional FEM based simulation process for normal glenoid bone remodeling was successfully created and validated. The element approach better predicted the actual specimen bone density distribution than the node. Some of the findings agreed with past studies that is, obtaining checkerboard pattern in the element approach. The various combinations of multiple loads had minimal effect on the predicted bone density distribution. The computer modeling, numerical stress analysis, and the simulated bone remodeling allowed successful glenoid structural analysis. The approach adopted improved our understanding of the glenoid prosthesis and successful shoulder arthroplasty.