<p>Current challenges in neuronal tract tracing include sacrificing the animal, detailed sectioning of the brain, and cumbersome reconstruction of slices to gather information, which are very tedious, time consuming, and have low-throughput. In this regard, Manganese-enhanced Magnetic Resonance Imaging (MEMRI) has been an emerging methodology for fiber tract tracing <i>in vivo</i>. <i></i>The manganese ion (Mn²⁺) is paramagnetic and is analogous to calcium ions (Ca²⁺), which allows it to enter excitable cells through voltage-gated calcium channels, thereby reporting cellular activity in T₁-weighted MR images<i>. </i>Moreover, once the Mn²⁺enters the cell, it will move along the axon by microtubules, release at the synapse, and then uptake by post-synaptic neurons, hence revealing the pathway of Mn²⁺transportation. While most MEMRI neuronal tracing studies have focused on mapping circuitries within the brain, MEMRI has rarely been applied to trace peripheral nerve projections into the brain. </p><p>In this thesis, I will propose the use of MEMRI to trace vagal nerve projections into the central nervous system by showing enhancement of neuronal pathways with an optimized protocol. This protocol demonstrates <i>in vivo </i>monitoring of manganese transport into the brain from the nodose ganglion and shows how the enhancement in MR images can be promoted with vagus nerve stimulation (VNS). Additionally, I will present preliminary findings, for the very first time, that show the downstream projection of the sympathetic pathway from the brainstem. In sum, the technique presented in this thesis will shed light on the use of MEMRI to study the functional results of using clinically-based VNS settings</p>

<div>Mesenchymal stem cells (MSCs) are responsive to mechanical stimuli that play an essential role in directing their differentiation to the chondrogenic lineage. A better</div><div>understanding of the mechanisms that allow MSCs to respond to mechanical stimuli is important to improving cartilage tissue engineering and regenerative medicine. Hydrostatic pressure (HP) in particular is known to be a primary mechanical force in joints. However, little is known about the underlying mechanisms that facilitate HP</div><div>mechanotransduction. Understanding the signaling pathways in MSCs in transducing HP to a beneficial biologic response and their interrelationship were the focus of this thesis. Studies used porcine marrow-derived MSCs seeded in agarose gel. Calcium ion Ca++ signaling, focal adhesion kinase (FAK) involvement, and sirtuin1 activity were investigated in conjunction with HP application.</div><div><br></div><div><div>Intracellular Ca++ concentration was previously shown to be changed with HP application. In our study a bioreactor was used to apply a single application of HP to the MSC-seeded gel structures and observe Ca++ signaling via live imaging of a fluorescent calcium indicator in cells. However, no fluctuations in Ca++ concentrations were observed with 10 minutes loading of HP. Additionally a problem with the biore actor design was discovered. First the gel was floating around in the bioreactor even without loading. After stabilizing the gel and stopping it from floating, there were still about 16 µm of movement and deformation in the system. The movement and deformation was analyzed for the gel structure and different parts of the bioreactor. </div><div><br></div><div>Furthermore, we investigated the role of FAK in early and late chondrogenesis and also its involvement in HP mechanotransduction. A FAK inhibitor was used on MSCs from day 1 to 21 and showed a dose-dependent suppression of chondrogenesis. However, when low doses of FAK inhibitor added to the MSC culture from day 21 to 42, chondrogenesis was not inhibited. With 4 hour cyclic HP, FAK phosphorylation increased. The beneficial effect of HP was suppressed with overnight addition of the</div></div><div><div>FAK inhibitor to MSC medium, suggesting FAK involvement in HP mechanotransducation by MSCs.</div></div><div><br></div><div>Moreover, sirtuin1 participation in MSC chondrogenesis and mechanotransduction was also explored. The results indicated that overnight sirtuin1 inhibition increased chondrogenic gene expression (Agc, Col2, and Sox9) in MSCs. Additionally, the activity of sirtuin1 was decreased with both 4 hour cyclic hydrostatic pressure and inhibitor application. These two together demonstrated that sirtuin1 inhibition enhances chondrogenesis.</div><div><br></div><div><div>In this research we have investigated the role of Ca++ signaling, FAK involvement, and sirtuin1 activity in the mechanotransduction of HP in MSCs. These understandings about the mechanisms regulating the chondrogenesis with respect to HP could have important implications for cartilage tissue engineering and regenerative studies.</div></div>

Computational modeling in the field of biomechanics is becoming increasingly popular and successful in practice for its ability to predict function and provide information that would otherwise be unobtainable. Through the application of these new and constantly improving methods, kinematics and joint contact characteristics in pathological conditions of femoroacetabular impingement (FAI) and total hip arthroplasty (THA) were studied using a lower extremity computational model. Patients presenting with FAI exhibit abnormal contact between the femoral neck and acetabular rim leading to surrounding tissue damage in daily use. THA is the replacement of both the proximal femur and acetabular region of the pelvis and is the most common surgical intervention for degenerative hip disorders. A combination of rigid osteoarticular anatomy and force vectors representing soft tissue structures were used in developing this model. Kinematics produced by healthy models were formally validated with experimental data from Burnfield et al. This healthy model was then modified to emulate the desired morphology of FAI and a THA procedure with a range of combined version (CV) angles. All soft tissue structures were maintained constant for each subsequent model. Data gathered from these models did not provide any significant differences between the kinematics of healthy and FAI but did show a large amount of variation in all THA kinematics including incidents of dislocation with cases of lower CV angles. With the results of these computational studies performed with this model, an increased understanding of hip morphology with regards to STS has been achieved.

In this study, a previously designed passive dynamic walker (PDW) is built out of aluminum and plastic. The aim of the study was to produce an asymmetrical PDW and to compare the results to a computer simulation to validate the mathematical model. It also aimed at identifying the limitations of using additive manufacturing to create components for a PDW as well as gain insights on asymmetric systems. Beginning with a five mass kneed model, parameters were varied to produce up to a nine mass kneed model solution. The nine mass model allows more variability in added mass locations and separates the zeroth, first, and second moments of inertia. To validate asymmetric gait, step length and step time of the prototype were compared to the simulation. The walker, unable to produce a steady gait, failed to match the asymmetric simulation. More than four times the amount of symmetric data was found compared to asymmetric data. Successful runs of symmetric gaits were approximately double than for asymmetric gaits. The reason for unequal successes is thought to be due to greater instability of asymmetric systems. This instability is thought to be due to inertia from a constant state of hanging motion. 3D printing proved useful in simplifying components and reducing waste but the polymers used did not have enough strength when mass was added to the system. Joining differing materials on the legs was difficult to keep in place. A smaller more robust design could solve these problems. This study focused on understanding physically asymmetric PDWs. These simple robots separate the neurological and mechanical controls of walking and are advantageous for studying physical parameters of human gait. Once a reliable asymmetric walker is built, further research could alter the foot shape or knee location to reverse the process, thus having a PDW walk symmetric. Once a walker is successfully reverted from walking asymmetrical to symmetrical, these parameters could be then applied to human subjects. An example of this would be for prosthetic foot design.

This dissertation describes the development and results of a physiological rigid body forward solution mathematical model that can be used to predict normal knee and total knee arthroplasty (TKA) kinematics and kinetics. The simulated activities include active extension and weight-bearing deep knee bend. The model includes both the patellofemoral and tibiofemoral joints. Geometry of the normal or implanted knee is represented by multivariate polynomials and modeled by constraining the velocity of lateral and medial tibiofemoral and patellofemoral contact points in a direction normal to the geometry surface. Center of mass, ligament and muscle attachment points and normal knee geometry were found using computer aided design (CAD) models built from computer tomography (CT) scans of a single subject. Quadriceps forces were the input for this model and were adjusted using a unique controller to control the rate of flexion, embedded with a controller which stabilizes the patellofemoral joint. The model was developed first using normal knee parameters. Once the normal knee model was validated, different total knee arthroplasty (TKA) designs were virtually implanted. The model was validated using in vivo data obtained through fluoroscopic analysis. In vivo data of the extension and deep knee bend activities from five non-implanted knees were used to validate the normal model kinematics. In vivo kinematic and kinetic data from a telemetric TKA with a tibia component instrumented with strain gauges was used to validate the kinematic and kinetic results of the model implanted with the TKA geometry. The tibiofemoral contact movement matched the trend seen in the in vivo data from the one patient available with this implant. The maximum axial tibiofemoral force calculated with the model was in 3.1% error with the maximum force seen in the in vivo data, and the trend of the contact forces matched well. Several other TKA designs were virtually implanted and analyzed to determine kinematics and bearing surface kinetics. The comparison between the model results and those previously assessed under in vivo conditions validates the effectiveness of the model and proves that it can be used to predict the in vivo kinematic and kinetic behavior of a TKA.

Heart failure is an important medical disease and impacts millions of people throughout the world. In order to treat this problem, biomaterial injectable treatment injected into the myocardium of the failing LV are currently being developed. Through this treatment, the biomaterial material injections can reduce wall stresses during the cardiac remodeling process. By using computational techniques to analyze the effects of a treatment involving the injection of biomaterial material into the LV after MI, the material parameters of the hydrogel injections can be optimized. The results shows that the hydrogel injections could reduce the global average fiber stress and the transmural average stress seen from optimization. These results indicated that the hydrogel injections could influence the stiffness in passive LV tissue, but there is still need for more research on the active part of ventricular contraction. Conclusion: hydrogel injection is a viable way to alter ventricular mechanical properties.

Myocardial infarctions induce a maladaptive ventricular remodeling process that independently contributes to heart failure. In order to develop effective treatments, it is necessary to understand the way and extent to which the heart undergoes remodeling over the course of healing. There have been few studies to produce any data on the in-vivo material properties of infarcts, and much less on the properties over the time course of healing. In this paper, the in-vivo passive material properties of an infarcted porcine model were estimated through a combined use of magnetic resonance imaging, catheterization, finite element modeling, and a genetic algorithm optimization scheme. The collagen fiber orientation at the epicardial and endocardial surfaces of the infarct were included in the optimization. Data from porcine hearts (N=6) were taken at various time points after infarction, specifically 1 week, 4 weeks, and 8 weeks post-MI. The optimized results shared similarities with previous studies. In particular, the infarcted region was shown to dramatically increase in stiffness at 1 week post-MI. There was also evidence of a subsequent softening of the infarcted region at later time points post infarction. Fiber orientation results varied greatly but showed a shift toward a more circumferential orientation.

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