This thesis introduces and presents the modeling of a novel compliant spinal implant designed to reduce back pain and restore function to degenerate spinal disc tissues as well as provide a mechanical environment conducive to healing the tissues. The initial objectives for this device development and the focus of this work are modeling and validation of the force-deflection relationships and stress analysis. Modeling was done using the pseudo-rigid-body model to create a 3 degree of freedom mechanism for flexion-extension (forward-backward bending) and a 5 degree of freedom mechanism for lateral bending (side-to-side). These models were analyzed using the principle of virtual work to obtain the force-deflection response of the device. The model showed good correlation to finite element analysis and experimental results. Also, described in this thesis is a model that incorporates an estimate of the combined stiffness of the biologic structures. This combined model is confirmed by cadaveric testing. A stress analysis of the implant for combined loading conditions is also presented. This work introduces and provides a foundation for the FlexSuRe™ spinal implant.

The human lumbar spine has been shown to support compressive loads of 1000 N in standing and walking, and up to many thousands of Newtons in strenuous activities such as lifting. The literature presents a number of biomechanical models that seek to replicate the load-carrying capacity of the spine while adhering to physiological constraints. While many of these models provide invaluable insights into the mechanisms governing spinal stability, there is a nearly universal disregard for the magnitude of the muscle forces required in the neutral standing posture. In compliance with constraints on metabolic cost and muscle fatigue, muscle activations in excess of 5% maximum voluntary contraction (MVC) in the standing posture are physiologically infeasible. The purpose of this thesis was to investigate the hypothesis that the passive structures of the lumbar spine are sufficient to produce static equilibrium under the body weight load in the neutral standing posture. A novel method of applying physiologic loads to the lumbar spine in vitro to determine its passive stability was developed. Five cadaver specimens were tested and a passive equilibrium posture was discovered for each. Further, the parameters defining the equilibrium posture correlate well with the standing posture as reported in the literature. This is an indication that the lumbar spine is inherently capable of remaining erect in the neutral posture with muscle activations below 5% MVC. It is postulated that the iliolumbar ligament and the thoracolumbar fascia, passive components that are not typically incorporated into stability models of the spine, have the potential to provide added passive stabilization to the system. It is recommended that biomechanical models of the spine incorporate this 5% MVC constraint and place greater emphasis on the contributions of passive structures to overall stability.

The purpose of this project is to quantify the effects of increasing spinal ligament fidelity on the mechanics of the human lumbar spine using finite element analysis (FEA). In support of this goal, a material characterization study was completed to provide anisotropic, nonlinear material parameters for the human anterior longitudinal ligament. (ALL). Cadaveric samples of the human ALL were tested using a punch test technique. Multi- axial force-deformation data were gathered and fit to a commonly used transversely isotropic material model using an FEA system identification routine. The resulting material parameters produced a curve that correlated well with the experimental curve (R2≥0.98). Recently published material data on several major spinal ligaments have been incorporated into an existing finite element model of the human lumbar spine. This data includes the results from the above mentioned material characterization, similar material characterizations of the supraspinous (SSL) and interspinous (ISL) ligaments, localized material properties of the SSL and pre-strain data for the ISL, SSL and ALL. These results have been incorporated both separately and compositely into the finite element model and each configuration has been simulated in spinal flexion, extension, axial rotation and lateral bending. Results suggest that the effects of increased ligament model fidelity on bone strain energy were moderate and the effects on disc pressure were slight, and do not justify a change in modeling strategy for most clinical applications. There were significant effects on the ligament stresses of the ligaments that were directly modified, suggesting that these phenomenon should be included in FE models where ligament stresses are the desired metric.

A neuropsychological examination is often used in tandem with other measures to confirm the diagnosis of idiopathic Normal Pressure Hydrocephalus (iNPH) and to assess improvement in cognitive functioning after a lumbar puncture test. Improvement in symptoms is thought to predict benefit from installation of a ventriculoperitoneal shunt that redirects CSF from the brain. Although the 72-hour external lumbar drain (ELD) has long been the gold-standard drainage procedure, hospitals are increasingly opting for the high-volume lumbar puncture, during which 50ml of CSF is released over an hour before the patient is tested for improvement in symptoms. The primary aims of this study were to evaluate the changes in cognitive performance produced by the two LP procedures and to compare the results produced by each procedure. In a review of medical records, 40 patients met criteria for inclusion. Cognitive functioning in the 72-hour ELD (n = 10) group was compared to changes in patients in the HVLP group, in terms of baseline level of functioning and post-drain changes. Statistical methods used to determine change included ANOVA and Reliable Change Indices. Dominant-hand Grooved Pegboard Test showed significant change after lumbar puncture, with higher mean change in the 72-hour ELD group. 72-hour ELD patients had a slightly higher rate of Reliable Change than HVLP patients. Cognitive changes were bi-directional in both groups. Results suggest that changes in cognitive functioning after lumbar puncture occur in a minority of patients, regardless of procedure type, and may have low predictive value for VPS benefit.

Indiana University-Purdue University Indianapolis (IUPUI) / Bisphosphonates, drugs which inhibit bone resorption and remodeling, are currently prescribed for the treatment of osteoporosis. Previous research suggests that decreased bone turnover may lead to accumulation of microdamage, possibly increasing the risk for fracture in some sites. The effects of bisphosphonate therapy on the mandibular condyle have not been quantitatively studied. The purpose of the proposed study was to histomorphometrically quantify the effects of etidronate (a bisphosphonate) on trabecular bone sites of the dog mandibular condyle and to compare this to another trabecular bone site (vertebrae) to determine whether the two sites were affected differently. Eleven mature female dogs were treated with high- (5 mg/kg/d) and low- (0.5 mg/kg/d) dose etidronate therapy for seven months. Fluorochrome labels were used to mark sites of bone mineralization for the calculation of static and dynamic histomorphometric parameters. High-dose therapy resulted in a complete inhibition of remodeling, as shown by the reduction of mineral apposition rate (MAR), bone formation rate (BFR), and mineralizing surface (MS/BS) to zero. Low-dose therapy also decreased BFR and MS/BS. Osteoid accumulation was only significant in the high-dose therapy group, but there was no evidence of osteomalacia (osteoid volume < 5%). Etidronate treatment had no significant effect on bone volume, trabecular number, trabecular thickness, or trabecular separation. Vertebral trabeculae ranged from 5.5 to 9.5 times greater in number than mandibular trabeculae, but were 45 to 60 percent thinner and closer together. The interaction between dosage and site was insignificant for all parameters studied. Further investigation is needed to determine whether these effects will prove to be harmful to the mandibular condyle, especially over a long period of time.

Autism spectrum disorders (ASDs) are a diverse class of neurodevelopmental disorders with various aberrant cellular phenotypes such as dysfunctional neurotransmission and irregular neuronal morphology. ASDs have a broad underlying genetic background with many genes linked to their etiology. UBE3A has been identified as a top gene candidate associated with ASD, and overexpression of UBE3A via copy-number variation confers hallmark ASD behaviors in humans and transgenic mice. Our previous work revealed that synapse formation was negatively affected in the Ube3A-ASD mouse model (Ube3A 2X Tg, or simply “2X Tg”). However, the cellular and molecular mechanisms underlying the synaptic dysregulation remain unknown. We sought to identify a cell-type specific mechanism by which these morphological changes were conferred. We found that selective overexpression of Ube3A in neurons failed to induce changes in dendritic spine maturation. In contrast, overexpression of Ube3A in astrocytes resulted in alterations in spines and synapses. Further, we identified thrombospondin-2 (TSP2), a secreted astrocytic glycoprotein promoting synaptogenesis and spinogenesis, is involved in the defective spine maturation. Ube3A overexpression confers a loss of transcriptional down-regulation of TSP2 in astrocytes, and the medium of astrocyte cultures with Ube3A overexpression was sufficient to trigger spine changes similar to that observed in mixed cultures that globally overexpress Ube3A. Importantly, depletion of TSP2 promoted similar loss of dendritic spine maturation, whereas supplement of TSP2 to 2X Tg astrocyte media was able to rescue the spine defects. Furthermore, overexpression of Ube3A in an astrocyte-specific manner recapitulated aberrant dendritic spine maturation as well as autism-like behaviors displayed in 2X Tg mice. Collectively, these findings reveal an astrocytic dominance in initiating ASD pathobiology at the neuronal and behavior levels.

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